OA Treatments Options

inflammatory plasma lipids and

Osteoarthritis Biomarkers and Treatments

2905-2915

1908-1917

1013-1017

2016;21:639-644

55:680-688

20

peripheral blood leukocyte biomarkers. Arthritis & Rheumatology. 2015;67:

clinical and radiographic changes at the knee joint. Osteoarthritis and Cartilage.

1997;5:87-97

[74] Attur M, Belitskaya-Lévy I, Oh C, Krasnokutsky S, Greenberg J, Samuels J, et al. Increased interleukin-1β gene expression in peripheral blood

leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis and Rheumatism. 2011;63:

[75] Attur M, Statnikov A, Samuels J, Li Z, Alekseyenko AV, Greenberg JD, et al. Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis. Osteoarthritis and Cartilage. 2015;23:1915-1924

[76] Bing W, Feng L. Attenuate synovial fluid uncarboxylated matrix Gla-protein (ucMGP) concentrations are linked with

[77] Mabey T, Honsawek S, Tanavalee A,

radiographic progression in knee osteoarthritis. Advances in Clinical and Experimental Medicine. 2015;24:

Yuktanandana P, Wilairatana V, Poovorawan Y. Plasma and synovial fluid inflammatory cytokine profiles in primary knee osteoarthritis. Biomarkers.

[78] Martel-Pelletier J, Raynauld JP, Dorais M, Abram F, Pelletier JP. The levels of the adipokines adipsin and leptin are associated with knee

MRI and incidence of total knee replacement in symptomatic osteoarthritis patients: A post hoc analysis. Rheumatology (Oxford). 2016;

[79] Dieppe PA, Cushnaghan J,

osteoarthritis progression as assessed by

Shepstone L. The Bristol 'OA 500'study: Progression of osteoarthritis (OA) over 3 years and the relationship between

**23**

**Chapter 2**

**Abstract**

**1. Introduction**

elderly people, and obese individuals [4].

Osteoarthritis as a Chronic

of the Inflammatory Markers

on the main inflammatory markers observed in studies with OA.

**Keywords:** osteoarthritis, immune response, inflammation, biomarkers, cytokines

Osteoarthritis (OA) is a common disease that can affect joints from any part of the body, and it represents a major cause of disability and joint pain worldwide [1, 2]. OA most commonly affects the knee, hip, and shoulder, and it was estimated that more than 25 million people in the USA were affected by some form of OA in the last decade [3]. In addition, OA presents a high susceptibility to affect female gender,

The progression of OA leads to cartilage degradation with subchondral bone remodeling, hypertrophy of the joint capsule, and osteophytes formation, causing pain [1, 5, 6]. Although the development of OA is considered a heterogeneous process, which comprises a number of genetic and environmental causes, the presence of local causes, such as trauma and hypermobility of the joint, may worsen OA [2, 7]. The accurate identification of osteoarthritic features has been studied in order to radiographically grade the stages of OA. The Kellgren-Lawrence classification is the most widely used, especially in clinical researches. This classification evaluates the appearance of osteophytes and cysts, joint space loss, and sclerosis, and it grades the severity from 0 to 5 points. The radiological features found in OA joints were

Inflammatory Disease: A Review

*José Fábio dos Santos Duarte Lana and Bruno Lima Rodrigues*

Osteoarthritis (OA) is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. In addition to macroscopic features, such as cartilage degradation with subchondral bone remodeling, hypertrophy of the joint capsule, and osteophytes formation, several cellular and molecular alterations are present in OA, which lead to a chronic low-grade inflammation. Inflammatory mediators observed in OA joints are thought to be the downstream effectors of the pathogenesis of the disease. Although cytokines are among the most extensively studied mediators of inflammation, such as IL-1β and TNF, there has been an increase in studies showing the contribution of chemokines and adipokines in OA progression. This fact is supported by recent progress, which has considerably improved knowledge of the factors involved in the development of OA and the mechanisms responsible for its progression. Therefore, the aim of this chapter is to discuss the involvement of the inflammatory response in OA maintenance, focusing

#### **Chapter 2**

## Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers

*José Fábio dos Santos Duarte Lana and Bruno Lima Rodrigues*

#### **Abstract**

Osteoarthritis (OA) is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. In addition to macroscopic features, such as cartilage degradation with subchondral bone remodeling, hypertrophy of the joint capsule, and osteophytes formation, several cellular and molecular alterations are present in OA, which lead to a chronic low-grade inflammation. Inflammatory mediators observed in OA joints are thought to be the downstream effectors of the pathogenesis of the disease. Although cytokines are among the most extensively studied mediators of inflammation, such as IL-1β and TNF, there has been an increase in studies showing the contribution of chemokines and adipokines in OA progression. This fact is supported by recent progress, which has considerably improved knowledge of the factors involved in the development of OA and the mechanisms responsible for its progression. Therefore, the aim of this chapter is to discuss the involvement of the inflammatory response in OA maintenance, focusing on the main inflammatory markers observed in studies with OA.

**Keywords:** osteoarthritis, immune response, inflammation, biomarkers, cytokines

#### **1. Introduction**

Osteoarthritis (OA) is a common disease that can affect joints from any part of the body, and it represents a major cause of disability and joint pain worldwide [1, 2]. OA most commonly affects the knee, hip, and shoulder, and it was estimated that more than 25 million people in the USA were affected by some form of OA in the last decade [3]. In addition, OA presents a high susceptibility to affect female gender, elderly people, and obese individuals [4].

The progression of OA leads to cartilage degradation with subchondral bone remodeling, hypertrophy of the joint capsule, and osteophytes formation, causing pain [1, 5, 6]. Although the development of OA is considered a heterogeneous process, which comprises a number of genetic and environmental causes, the presence of local causes, such as trauma and hypermobility of the joint, may worsen OA [2, 7].

The accurate identification of osteoarthritic features has been studied in order to radiographically grade the stages of OA. The Kellgren-Lawrence classification is the most widely used, especially in clinical researches. This classification evaluates the appearance of osteophytes and cysts, joint space loss, and sclerosis, and it grades the severity from 0 to 5 points. The radiological features found in OA joints were

graded as follows: (1) formation of osteophytes on joint margins or on tibia spines for knee OA; (2) periarticular ossicles in relation to distal and proximal interphalangeal joints; (3) narrowing of joint cartilage and sclerosis of subchondral bone; (4) pseudocystic areas with sclerotic walls in the subchondral bone; and (5) altered shape of the bone ends [8]. Some of these criteria were adopted by the World Health Organization (WHO) as the standard for studies on OA.

Current options for the treatment of OA focus on reducing pain (non-steroidal anti-inflammatory drugs—NSAIDs) and joint viscosupplementation (intraarticular injections of hyaluronic acid) [1]. Besides presenting a short-term effect, the chronic use of some of these medications, especially NSAIDs, may cause serious adverse events, including toxicity and risk of thromboembolism [9, 10]. In severe cases, surgical procedures, mostly joint replacement, are suggested [1]. Novel alternative therapies, called orthobiologics, have emerged from the need of tissue regeneration. Clinical trials using orthobiologics, which comprise platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), fat graft (Biofat), and expanded mesenchymal stem cells, have shown promising results for the treatments of OA from any origin [11–14].

Moreover, monoclonal antibody (mAb) therapy represents one of the alternative treatments that aim to control inflammation and slow structural progression [15]. This approach focuses on blocking specific molecules responsible for the maintenance of OA. Preclinical studies with ADAMTS mAbs reported a significant decrease in histological scores after 3 months of treatment [16]. Adalimumab is an anti-TNF-α therapy used in diverse immune-mediated diseases, and it presents a protective role for OA as it reduces the severity of the cartilage lesion and improves the structure of subchondral bone [17]. Since IL-1 family may induces the production of metalloproteinases (MMP), it has also become a target for mAb therapy, and, in a randomized controlled trial with patients who presented knee OA, it was reported great improvement on pain relief [18].

In addition to macroscopic features, several cellular and molecular alterations are present in OA, such as catabolism and anabolism events; hypertrophy and, consequently, death of chondrocytes; and impaired autophagy process [19]. Also, a chronic low-grade inflammation interplayed with immune system has been considered to present a crucial role in the maintenance of OA [1]. This fact is supported by recent progress, which has considerably improved the knowledge regarding factors involved in the OA development and the mechanisms responsible for its progression.

#### **2. Osteoarthritis and immune response**

The inflammation observed in OA is believed to involve innate immune response prior to a mild degree of adaptive immunity [20]. During tissue damage, a group of endogenous molecules, called damage-associated molecular pattern (DAMP), signals the immune cells to induce a protective response against the tissue, causing tissue repair. However, a prolonged signaling of DAMP to immune cells leads to an exacerbated cytokine release, which can be destructive to the tissue [21, 22].

Innate immune cells activated by DAMP include macrophages and mast cells, which have shown to present (displayed or demonstrated) a key role in the pathogenesis of OA. Mast cells are considered regulators of vascular permeability, and they may play a crucial role in OA joint inflammation as they facilitate leukocyte infiltration [23].

Macrophages exhibit a functional plasticity based on the environment in which they are located or present [22]. However, their chronic activation can lead to the

**25**

markers [38].

esis in OA.

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

production of proinflammatory cytokines, which worsen the osteoarthritic joints [24]. *In vitro* studies of human OA synovium-derived cells showed that macrophage depletion results in diminishing of inflammatory response by decrease of proteolytic enzyme expression, such as metalloproteinases (MMP) This fact is supported by *in vitro* studies with cell culture suspension of human OA synovium, which reported that, after macrophage depletion, there was a decrease in the production of inflammatory response by less activity of proteolytic enzymes, such as metalloproteinases (MMP) [25]. Although macrophages may also present a protective role, as they are known to secrete transforming growth factor β (TGF-β), which would enhance cartilage repair, intra-articular injection of TGF-β in mice knee led

In addition, natural killer (NK) infiltrates are commonly found in synovial tissue from patients who underwent joint replacement surgeries, and a subset of NK cells (CD56bright) was found to be greatly expanded in patients with inflammatory arthritis who have not undergone joint replacement surgeries. However, the effect of these cells on the development of OA has not been elucidated yet [27–29]. NK cells secrete protease enzymes called granzyme type A and B, which correlate to cytolytic potency. Granzymes can be released during degranulation of cytotoxic cells and, when delivered intracellularly to the target cells, they induce apoptosis. Granzyme A also stimulates the production of tumor necrosis factor (TNF-α), IL-6, and IL-8, while granzyme B may intensify the degradation of extracellular matrix [30, 31]. Tak et al. identified both types of granzymes in synovia from OA and rheumatoid arthritis. However, another study later showed that NK cells within OA synovia were granzyme negative with potential to produce the interferon-γ (IFN-γ) when expanded with IL-2 and stimulated with cytokines known to trigger IFN-γ

The presence of IFN-γ has a role in the bone resorption and consequently in the osteoclastogenesis process, but the studies have shown controversial results in this regard: *in vitro* evidence reported that IFN-γ, via TRANCE pathway, strongly suppresses osteoclastogenesis in culture of mononuclear phagocyte cells, which are the osteoclast precursors [33], whereas in culture of peripheral blood it may enhance osteoclast production as IFN-γ increases superoxide generation by neutrophils [34]. In addition, experimental studies in which IFN-γ receptor was silenced suggested a more rapid onset of collagen-induced arthritis [35]. Although IFN-γ plays a key role in angiogenesis, there is no evidence that this cytokine is able to promote angiogen-

Proteins from complement system have been found to play a role in OA, especially in early stages, as they were upregulated in both synovial membrane and fluid [23, 36]. Additionally, the deposition of the membrane attack complex (MAC, C5b-9) is correlated with the presence of inflammation on histology of synovial membrane, and it was present in chondrocytes in late OA [36]. MAC can lead to chondrocyte destruction as it stimulates catabolic events through the increase of leukocytes and, consequently, the production of MMP [23]. Also in the studies with experimental

Cellular infiltrates from adaptive immune response have also been observed in synovial fluid from OA joints. Although the main cell type present in this infiltrate is CD3+ T cells, both CD4+ and CD8+ cells have also been found in OA [37]. Th1 cells, and consequently their secretory cytokines, such as IL-2 and INF-γ, appear to be expressed five times greater than Th2 in most of OA patients [37]. Based on lymphocyte aggregates, there is a suggestion of an active cell-mediated immune response since T-cells in lymphocytic aggregates in OA synovium were shown to bear early (CD69), intermediate (CD25 and CD38), and late (CD45RO) activation

knockout models for C5 and C6, the joint damages were attenuated [36].

production in blood NK cells, such as IL-12 and IL-18 [27, 32].

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

to osteophyte formation and fibrosis [26].

#### *Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

production of proinflammatory cytokines, which worsen the osteoarthritic joints [24]. *In vitro* studies of human OA synovium-derived cells showed that macrophage depletion results in diminishing of inflammatory response by decrease of proteolytic enzyme expression, such as metalloproteinases (MMP) This fact is supported by *in vitro* studies with cell culture suspension of human OA synovium, which reported that, after macrophage depletion, there was a decrease in the production of inflammatory response by less activity of proteolytic enzymes, such as metalloproteinases (MMP) [25]. Although macrophages may also present a protective role, as they are known to secrete transforming growth factor β (TGF-β), which would enhance cartilage repair, intra-articular injection of TGF-β in mice knee led to osteophyte formation and fibrosis [26].

In addition, natural killer (NK) infiltrates are commonly found in synovial tissue from patients who underwent joint replacement surgeries, and a subset of NK cells (CD56bright) was found to be greatly expanded in patients with inflammatory arthritis who have not undergone joint replacement surgeries. However, the effect of these cells on the development of OA has not been elucidated yet [27–29]. NK cells secrete protease enzymes called granzyme type A and B, which correlate to cytolytic potency. Granzymes can be released during degranulation of cytotoxic cells and, when delivered intracellularly to the target cells, they induce apoptosis. Granzyme A also stimulates the production of tumor necrosis factor (TNF-α), IL-6, and IL-8, while granzyme B may intensify the degradation of extracellular matrix [30, 31]. Tak et al. identified both types of granzymes in synovia from OA and rheumatoid arthritis. However, another study later showed that NK cells within OA synovia were granzyme negative with potential to produce the interferon-γ (IFN-γ) when expanded with IL-2 and stimulated with cytokines known to trigger IFN-γ production in blood NK cells, such as IL-12 and IL-18 [27, 32].

The presence of IFN-γ has a role in the bone resorption and consequently in the osteoclastogenesis process, but the studies have shown controversial results in this regard: *in vitro* evidence reported that IFN-γ, via TRANCE pathway, strongly suppresses osteoclastogenesis in culture of mononuclear phagocyte cells, which are the osteoclast precursors [33], whereas in culture of peripheral blood it may enhance osteoclast production as IFN-γ increases superoxide generation by neutrophils [34]. In addition, experimental studies in which IFN-γ receptor was silenced suggested a more rapid onset of collagen-induced arthritis [35]. Although IFN-γ plays a key role in angiogenesis, there is no evidence that this cytokine is able to promote angiogenesis in OA.

Proteins from complement system have been found to play a role in OA, especially in early stages, as they were upregulated in both synovial membrane and fluid [23, 36]. Additionally, the deposition of the membrane attack complex (MAC, C5b-9) is correlated with the presence of inflammation on histology of synovial membrane, and it was present in chondrocytes in late OA [36]. MAC can lead to chondrocyte destruction as it stimulates catabolic events through the increase of leukocytes and, consequently, the production of MMP [23]. Also in the studies with experimental knockout models for C5 and C6, the joint damages were attenuated [36].

Cellular infiltrates from adaptive immune response have also been observed in synovial fluid from OA joints. Although the main cell type present in this infiltrate is CD3+ T cells, both CD4+ and CD8+ cells have also been found in OA [37]. Th1 cells, and consequently their secretory cytokines, such as IL-2 and INF-γ, appear to be expressed five times greater than Th2 in most of OA patients [37]. Based on lymphocyte aggregates, there is a suggestion of an active cell-mediated immune response since T-cells in lymphocytic aggregates in OA synovium were shown to bear early (CD69), intermediate (CD25 and CD38), and late (CD45RO) activation markers [38].

*Osteoarthritis Biomarkers and Treatments*

of OA from any origin [11–14].

reported great improvement on pain relief [18].

**2. Osteoarthritis and immune response**

Organization (WHO) as the standard for studies on OA.

graded as follows: (1) formation of osteophytes on joint margins or on tibia spines for knee OA; (2) periarticular ossicles in relation to distal and proximal interphalangeal joints; (3) narrowing of joint cartilage and sclerosis of subchondral bone; (4) pseudocystic areas with sclerotic walls in the subchondral bone; and (5) altered shape of the bone ends [8]. Some of these criteria were adopted by the World Health

Current options for the treatment of OA focus on reducing pain (non-steroidal

Moreover, monoclonal antibody (mAb) therapy represents one of the alternative treatments that aim to control inflammation and slow structural progression [15]. This approach focuses on blocking specific molecules responsible for the maintenance of OA. Preclinical studies with ADAMTS mAbs reported a significant decrease in histological scores after 3 months of treatment [16]. Adalimumab is an anti-TNF-α therapy used in diverse immune-mediated diseases, and it presents a protective role for OA as it reduces the severity of the cartilage lesion and improves the structure of subchondral bone [17]. Since IL-1 family may induces the production of metalloproteinases (MMP), it has also become a target for mAb therapy, and, in a randomized controlled trial with patients who presented knee OA, it was

In addition to macroscopic features, several cellular and molecular alterations are present in OA, such as catabolism and anabolism events; hypertrophy and, consequently, death of chondrocytes; and impaired autophagy process [19]. Also, a chronic low-grade inflammation interplayed with immune system has been considered to present a crucial role in the maintenance of OA [1]. This fact is supported by recent progress, which has considerably improved the knowledge regarding factors involved in the OA development and the mechanisms responsible for its

The inflammation observed in OA is believed to involve innate immune response prior to a mild degree of adaptive immunity [20]. During tissue damage, a group of endogenous molecules, called damage-associated molecular pattern (DAMP), signals the immune cells to induce a protective response against the tissue, causing tissue repair. However, a prolonged signaling of DAMP to immune cells leads to an exacerbated cytokine release, which can be destructive to the tissue [21, 22].

Innate immune cells activated by DAMP include macrophages and mast cells, which have shown to present (displayed or demonstrated) a key role in the pathogenesis of OA. Mast cells are considered regulators of vascular permeability, and they may play a crucial role in OA joint inflammation as they facilitate leukocyte

Macrophages exhibit a functional plasticity based on the environment in which they are located or present [22]. However, their chronic activation can lead to the

anti-inflammatory drugs—NSAIDs) and joint viscosupplementation (intraarticular injections of hyaluronic acid) [1]. Besides presenting a short-term effect, the chronic use of some of these medications, especially NSAIDs, may cause serious adverse events, including toxicity and risk of thromboembolism [9, 10]. In severe cases, surgical procedures, mostly joint replacement, are suggested [1]. Novel alternative therapies, called orthobiologics, have emerged from the need of tissue regeneration. Clinical trials using orthobiologics, which comprise platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), fat graft (Biofat), and expanded mesenchymal stem cells, have shown promising results for the treatments

**24**

infiltration [23].

progression.

#### **3. Inflammatory markers in osteoarthritis**

#### **3.1 Cytokines**

Inflammatory mediators observed in OA joints are thought to be the downstream effectors of the pathogenesis of the disease. Cytokines are among the most extensively studied mediators of inflammation. Several cytokines have been reported to play a role in the progression of OA, such as TNF, IL-1β, IL-6, IL-15, IL-17, IL-18, IL-4, and IL-10. Although their precise mechanism of action has not been completely elucidated yet, it has been proposed that their presence influences cartilage homeostasis as they induce catabolic events as well as inhibit anabolic processes [21, 39, 40].

#### *3.1.1 IL-1β and TNF*

Interleukin (IL)-1β and tumor necrosis factor (TNF) are considered the major mediators in the pathophysiology of OA. They both are secreted not only by immune cells, especially mononuclear cells, but also by chondrocytes and osteoblasts. In OA joints, these cytokines are increased in both synovial fluid and membrane. They are known to drive the inflammatory cascade, and their increased expression induces catabolic events as they enhance MMP [39]. IL-1β and TNF downregulate the synthesis of major extracellular matrix (ECM) components by inhibiting anabolic activities of chondrocytes [40] and reducing type II collagen production [41].

IL-1β is activated through the binding of its specific receptor type I (IL-1RI). Overexpression of IL-1RI in cartilage proximal to the macroscopic injury in OA joints resulting in increased binding of IL-1β was observed [42]. IL-1β has also been reported to be responsible for the catabolic events present in OA: its expression combined with TNF induces the production of MMP-1, -3, and -13 and stimulates the production of aggrecanases (ADAMTS)-4 and -5 in human and bovine chondrocytes [43, 44]. TNF receptor type I (TNFRI) is overexpressed in OA chondrocytes [45]. High levels of TNF-α in cartilage explants seem to inhibit the synthesis of proteoglycan and stimulate resorption [40].

In OA joint, IL-1β and TNF amplify the arthritic condition by inducing the production of proinflammatory cytokines, such as IL-6, IL-8, and monocyte chemoattractant protein 1. In addition, chondrocytes treated with IL-1β and TNF increase the production of nitric oxide (NO), cyclooxygenase 2 (COX-2), and prostaglandin E2 (PGE2), which contribute to articular inflammation and cartilage destruction as they enhance MMP activity, inhibit the production of anabolic products such as collagen and proteoglycan, and induce chondrocyte apoptosis [39].

The catabolic events observed (the catabolic events that occur due to the presence of…) in the presence of IL-1β and TNF are mediated through the activation of signaling pathways, including nuclear factor-κB (NF-κB) signaling. NF-κB pathway induces the expression of the genes related to the inflammatory mediators cited above and also contributes to the induction of MMP-1 and -13 and ADAMTS-4 [46]. However, some signaling pathways are involved in the downregulation of the IL-1β and TNF effects in OA, such as peroxisome proliferator-activated receptor-γ (PPAR-γ). The activation of PPAR-γ seems to reduce the progression of cartilage lesion in experimental models of OA as it assists the downregulation of inflammatory and catabolic responses mediated by IL-1β and TNF [47, 48].

#### *3.1.2 IL-6*

IL-6 is a proinflammatory cytokine, whose signaling pathway involves the activation of receptors, such as membrane-bound IL-6 receptor (IL6R), soluble

**27**

*3.1.5 IL-18*

*3.1.3 IL-15*

*3.1.4 IL-17*

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

IL-6R (sIL-6R), and gp130, followed by the activation of STAT1 and STAT3 pathways [39]. In physiological conditions, the production of IL-6 by chondrocytes is considerably low. However, the exact mechanism of IL-6 action in OA is unknown, but its production can be stimulated by the number of cytokines and growth factors

Increased levels of IL-6 in synovial fluid and serum have been correlated with

One of the most considered active components in OA is the change in subchondral bone tissue, and IL-6 has been a critical mediator in this regard. Its effect, together with IL-1β and TNF, is based on promoting osteoclast formation and, consequently, bone resorption [55]. In response to IL-6, osteoblasts stimulate the production of receptor activator of NF-κB ligand, IL-1β, and PGE2, which activate osteoclasts [56]. In addition, osteoblasts activated by these cytokines produce

Despite a better documented involvement in rheumatoid arthritis [58], the knowledge regarding IL-15 and its action in OA is still poor. It acts based on the stimulation and proliferation of T cells and NK cells, and it may also induce the production of MMP [59]. IL-15 levels are elevated in synovial fluid in early stages of OA, and this concentration correlates with pain and severity of lesions seen on X-ray imaging [60, 61].

Due to its inflammatory effects, IL-17 family has been implied to play a role in OA [62]. IL-17 is mainly stimulated by CD4+ T cells and mast cells, which are present in the cellular infiltrates observed in OA joints [63]. Within the joints, IL-17 primarily targets chondrocytes and fibroblast-like synoviocytes, which express IL-17 receptor (IL-17R) on their surface [64]. It was reported that IL-17 is able to inhibit proteoglycan synthesis by chondrocytes and increase the production of MMPs [65]. Also, high levels of IL-17 in both serum and synovial fluid were cor-

The genetic correlation between IL-17 and OA was suggested: a polymorphism in the gene IL-17A G-197A could be associated with the susceptibility to the development of OA [67]. In addition, IL-17 is produced by a specific T cell lineage called T helper 17, and it is able to cause hypertrophy of synovial membrane as its presence influences the secretion of vascular endothelial growth factor (VEGF), which leads to excessive blood vessel formation [68]. It can also indirectly affect cartilage by inducing the production of cytokines responsible for tissue degradation, such as

The active form of IL-18 results from the activation of caspase-1, which has been reported to be elevated in articular cartilage and synovium of OA, leading to great

the severity of lesions in X-ray imaging [50]. *In vitro* studies have shown that IL-6, in combination with IL-1β and TNF, upregulates the production of MMP-1 and -13 in human and bovine chondrocytes and induces proteoglycan and type II collagen degradation [51, 52]. The effect of IL-6 in studies with animal models has shown uncertain results. IL-6 knockout mice revealed more advanced degenerative changes compared to wild-type animals [53]. However, when IL-6 was injected in the joint cavity of IL-6-deficient mice, the reduction in the loss of proteoglycans in

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

present in OA, including IL-1β, TGF-β, and PGE2 [25, 49].

the acute phase of inflammation was observed [54].

related with radiographic lesions in OA [66].

IL-1β, TNF, IL-6, NO, and PGE2 [64].

MMPs, which adversely affect the surrounding cartilage [57].

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

IL-6R (sIL-6R), and gp130, followed by the activation of STAT1 and STAT3 pathways [39]. In physiological conditions, the production of IL-6 by chondrocytes is considerably low. However, the exact mechanism of IL-6 action in OA is unknown, but its production can be stimulated by the number of cytokines and growth factors present in OA, including IL-1β, TGF-β, and PGE2 [25, 49].

Increased levels of IL-6 in synovial fluid and serum have been correlated with the severity of lesions in X-ray imaging [50]. *In vitro* studies have shown that IL-6, in combination with IL-1β and TNF, upregulates the production of MMP-1 and -13 in human and bovine chondrocytes and induces proteoglycan and type II collagen degradation [51, 52]. The effect of IL-6 in studies with animal models has shown uncertain results. IL-6 knockout mice revealed more advanced degenerative changes compared to wild-type animals [53]. However, when IL-6 was injected in the joint cavity of IL-6-deficient mice, the reduction in the loss of proteoglycans in the acute phase of inflammation was observed [54].

One of the most considered active components in OA is the change in subchondral bone tissue, and IL-6 has been a critical mediator in this regard. Its effect, together with IL-1β and TNF, is based on promoting osteoclast formation and, consequently, bone resorption [55]. In response to IL-6, osteoblasts stimulate the production of receptor activator of NF-κB ligand, IL-1β, and PGE2, which activate osteoclasts [56]. In addition, osteoblasts activated by these cytokines produce MMPs, which adversely affect the surrounding cartilage [57].

#### *3.1.3 IL-15*

*Osteoarthritis Biomarkers and Treatments*

**3.1 Cytokines**

*3.1.1 IL-1β and TNF*

**3. Inflammatory markers in osteoarthritis**

proteoglycan and stimulate resorption [40].

Inflammatory mediators observed in OA joints are thought to be the downstream effectors of the pathogenesis of the disease. Cytokines are among the most extensively studied mediators of inflammation. Several cytokines have been reported to play a role in the progression of OA, such as TNF, IL-1β, IL-6, IL-15, IL-17, IL-18, IL-4, and IL-10. Although their precise mechanism of action has not been completely elucidated yet, it has been proposed that their presence influences cartilage homeostasis as they induce catabolic events as well as inhibit anabolic processes [21, 39, 40].

Interleukin (IL)-1β and tumor necrosis factor (TNF) are considered the major mediators in the pathophysiology of OA. They both are secreted not only by immune cells, especially mononuclear cells, but also by chondrocytes and osteoblasts. In OA joints, these cytokines are increased in both synovial fluid and membrane. They are known to drive the inflammatory cascade, and their increased expression induces catabolic events as they enhance MMP [39]. IL-1β and TNF downregulate the synthesis of major extracellular matrix (ECM) components by inhibiting anabolic activities of chondrocytes [40] and reducing type II collagen production [41]. IL-1β is activated through the binding of its specific receptor type I (IL-1RI). Overexpression of IL-1RI in cartilage proximal to the macroscopic injury in OA joints resulting in increased binding of IL-1β was observed [42]. IL-1β has also been reported to be responsible for the catabolic events present in OA: its expression combined with TNF induces the production of MMP-1, -3, and -13 and stimulates the production of aggrecanases (ADAMTS)-4 and -5 in human and bovine chondrocytes [43, 44]. TNF receptor type I (TNFRI) is overexpressed in OA chondrocytes [45]. High levels of TNF-α in cartilage explants seem to inhibit the synthesis of

In OA joint, IL-1β and TNF amplify the arthritic condition by inducing the production of proinflammatory cytokines, such as IL-6, IL-8, and monocyte chemoattractant protein 1. In addition, chondrocytes treated with IL-1β and TNF increase the production of nitric oxide (NO), cyclooxygenase 2 (COX-2), and prostaglandin E2 (PGE2), which contribute to articular inflammation and cartilage destruction as they enhance MMP activity, inhibit the production of anabolic products such as

The catabolic events observed (the catabolic events that occur due to the presence of…) in the presence of IL-1β and TNF are mediated through the activation of signaling pathways, including nuclear factor-κB (NF-κB) signaling. NF-κB pathway induces the expression of the genes related to the inflammatory mediators cited above and also contributes to the induction of MMP-1 and -13 and ADAMTS-4 [46]. However, some signaling pathways are involved in the downregulation of the IL-1β and TNF effects in OA, such as peroxisome proliferator-activated receptor-γ (PPAR-γ). The activation of PPAR-γ seems to reduce the progression of cartilage lesion in experimental models of OA as it assists the downregulation of inflamma-

IL-6 is a proinflammatory cytokine, whose signaling pathway involves the activation of receptors, such as membrane-bound IL-6 receptor (IL6R), soluble

collagen and proteoglycan, and induce chondrocyte apoptosis [39].

tory and catabolic responses mediated by IL-1β and TNF [47, 48].

**26**

*3.1.2 IL-6*

Despite a better documented involvement in rheumatoid arthritis [58], the knowledge regarding IL-15 and its action in OA is still poor. It acts based on the stimulation and proliferation of T cells and NK cells, and it may also induce the production of MMP [59]. IL-15 levels are elevated in synovial fluid in early stages of OA, and this concentration correlates with pain and severity of lesions seen on X-ray imaging [60, 61].

#### *3.1.4 IL-17*

Due to its inflammatory effects, IL-17 family has been implied to play a role in OA [62]. IL-17 is mainly stimulated by CD4+ T cells and mast cells, which are present in the cellular infiltrates observed in OA joints [63]. Within the joints, IL-17 primarily targets chondrocytes and fibroblast-like synoviocytes, which express IL-17 receptor (IL-17R) on their surface [64]. It was reported that IL-17 is able to inhibit proteoglycan synthesis by chondrocytes and increase the production of MMPs [65]. Also, high levels of IL-17 in both serum and synovial fluid were correlated with radiographic lesions in OA [66].

The genetic correlation between IL-17 and OA was suggested: a polymorphism in the gene IL-17A G-197A could be associated with the susceptibility to the development of OA [67]. In addition, IL-17 is produced by a specific T cell lineage called T helper 17, and it is able to cause hypertrophy of synovial membrane as its presence influences the secretion of vascular endothelial growth factor (VEGF), which leads to excessive blood vessel formation [68]. It can also indirectly affect cartilage by inducing the production of cytokines responsible for tissue degradation, such as IL-1β, TNF, IL-6, NO, and PGE2 [64].

#### *3.1.5 IL-18*

The active form of IL-18 results from the activation of caspase-1, which has been reported to be elevated in articular cartilage and synovium of OA, leading to great

promotion of IL-18 and IL-1β. The production of IL-18 in joints is mainly determined by chondrocytes, osteoblasts, and macrophages [69]. IL-18 affects cartilage by upregulating the production of IL-18Rα on chondrocyte surface and stimulates excessive production of MMP-1, -3, and -13 [70]. Also, IL-18 negatively influences the production of proteoglycans, aggrecan, and type II collagen and may cause morphological changes typically observed in apoptotic processes [71, 72].

The increased concentration of IL-18 observed in synovial fluid, synovium, cartilage, and even blood serum from patients with OA has been correlated with the severity of lesions seen in radiographic imaging [73]. Also, studies have correlated the development of OA and lumbar disc degeneration with polymorphisms in the gene encoding IL-18 and its receptor (IL-18R) [74, 75].

#### *3.1.6 IL-4*

Anti-inflammatory cytokines also present a role in the maintenance of OA. IL-4 is associated with chondroprotective effects as it is shown to reduce MMP production and, consequently, inhibit the degradation of proteoglycans in the articular cartilage [76]. However, chondrocytes from OA joints have shown a decreased susceptibility to this IL-4 protective effect, leaving the cartilage unprotected, quickening the degeneration via the action of the proinflammatory cytokines cited above [77]. In addition, a polymorphism in the gene encoding IL-4 and its main receptor (IL-4Rα) could predetermine the development of OA in hand and knee joints [78, 79]. It was also further reported that, when compared with healthy patients, OA patients present an elevated level of soluble IL-4Rα (sIL-4Rα) [80].

The activation of IL-4 depends on intracellular signal transduction by gradual phosphorylation of IL-4Rα, which leads to the expression of several proinflammatory genes [81]. IL-4 production is mainly determined by T cells, especially Th2, which are present in the cellular infiltrates observed in OA [37]. It was reported that IL-4 alone or in combination with IL-10 is able to reduce the production of diverse proinflammatory mediators, such as IL-1β, TNF-α receptors, IL-6, PGE2, and COX-2 [82–84].

#### *3.1.7 IL-10*

Due to its anti-inflammatory features, IL-10 is another cytokine that presents chondroprotective effects, and it is linked to the release of IFN [62]. *In vitro* studies have shown increased proteoglycan and type II collagen syntheses after the administration of IL-10 in chondrocytes [62]. The protective effects that IL-10 exhibits are likely due to a stimulation of the synthesis of IL-1β antagonist and a tissue inhibition of MMP-1 (TIMP-1) [85]. Also, IL-10, as well as IL-4, reduces apoptotic events in chondrocytes and production of MMP [86, 87].

IL-10 induces the expression of bone morphogenetic protein-2 and -6 (BMP2 and BMP6), which are related to chondrogenesis as they belong to TGF-β family [88]. Together with BMP production, IL-10 activates signaling pathways, such as NKX-3.2/SOX9, that induce the differentiation of mesenchymal stem cells into chondrocytes [89]. Also, by reducing the expression of TNF-α receptors, IL-10 is able to attenuate the effect of TNF-α on synovial fibroblasts. A decrease in COX-2 production was also noted in the same study [90].

The secretion of IL-10 can be influenced by physical exercises. Patients with and without OA had synovial fluid and periarticular tissue harvested from their knee before, during, and after they underwent exercise practice for 3 hours. A significant increase in IL-10 levels was observed in these patients after the exercise. Although it is not clear what exact mechanism led to this result, this observation is

**29**

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

likely attributed to an increase in intra-articular pressure and subsequent effects on

Chemokines comprise small proteins that act as chemoattractants to assist cells to migrate to injured tissue. Diverse chemokines have gained attention in the development of OA. Some of them including their receptors, such as IL-8, CCL5, CCL19, CCR1, CCR2, CCR3, and CCR5, may induce the production of MMP-3 by chondrocytes and increase the breakdown of cartilage matrix components, which trigger the onset of OA [60, 93]. However, some chemokines might present a protective role in OA, such as stromal cell-derived factor-1 (also called CXCL12), whose main function is to recruit mesenchymal stem cells to the injured area in order to promote

Several chemokines were reported to be overexpressed in OA, such as IL-8/ CXCL-8, GROα/CXCL-1, MCP-1/CCL-2, RANTES/CCL-5, MIP-1α/CCL-3, and MIP-1β/CCL-4. Some of these chemokines are stimulated by IL-1β, which is

upregulated in OA, and they induce MMP production upon binding to their ligands, causing tissue degradation [93]. Levels of INF-γ-inducible protein 10 (IP-10), also called as CXCL-10, in plasma and synovial fluid have been correlated with radiographic knee OA. CX3CL1, a serum fractalkine, has also been reported to be significantly elevated in severe knee OA in a study that compared OA patients with

To support the role of macrophage in the inflammatory response observed in OA, MCP-1, also known as chemokine ligand-2 (CCL2), has been reported to recruit macrophages into adipose tissue and atherosclerotic lesions [96]. Also, MCP-1 levels in both serum and synovial fluid has been associated with selfreported pain and disability in patients who present knee OA [97]. In addition, it was observed that, in severe knee OA, the levels of macrophage-derived chemokine (MDC) and IP-10 in synovial fluid were elevated, while eotaxin levels, an eosinophil chemotactic protein, were lower when compared with healthy patients [98].

Adipokines have been associated with the incidence and severity of OA [99]. *In vitro* studies reported that the presence of adipokines, such as leptin, adiponectin, visfatin, and resistin, increases the production of inflammatory mediators and also induces chondrolysis [99]. Although the exact mechanism of how these cytokines derived from adipose tissue act on arthritic joints has not yet been elucidated, researchers have studied the role of fat pad as a local inflammation mediator in OA, particularly in knee OA due to the infrapatellar fat pad, which has proven to be infiltrated with macrophages, lymphocytes, and granulocytes [100]. These findings support the thought that obesity supports the development of OA more through biochemical pathways rather than biomechanical overload risks on a weight-bearing joint.

The COX-2 enzyme is responsible for the production of lipid mediators, including PGE2 and leukotrienes, and it is also upregulated in OA joints. In addition, the overexpression of COX-2 in OA has been associated with the increased production of IL-1β, TNF, and IL-6 via toll-like receptor-4 (TLR-4) [101]. Besides assisting the production of MMPs and other functions already cited above, PGE2 is also involved

in apoptosis and structural changes that characterize arthritic disease [102].

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

cellular secretion [91, 92].

**3.2 Chemokines**

tissue repair [94].

healthy patients [95].

**3.3 Adipokines**

**3.4 Lipid mediators**

likely attributed to an increase in intra-articular pressure and subsequent effects on cellular secretion [91, 92].

#### **3.2 Chemokines**

*Osteoarthritis Biomarkers and Treatments*

*3.1.6 IL-4*

COX-2 [82–84].

*3.1.7 IL-10*

promotion of IL-18 and IL-1β. The production of IL-18 in joints is mainly determined by chondrocytes, osteoblasts, and macrophages [69]. IL-18 affects cartilage by upregulating the production of IL-18Rα on chondrocyte surface and stimulates excessive production of MMP-1, -3, and -13 [70]. Also, IL-18 negatively influences the production of proteoglycans, aggrecan, and type II collagen and may cause morphological changes typically observed in apoptotic processes [71, 72].

The increased concentration of IL-18 observed in synovial fluid, synovium, cartilage, and even blood serum from patients with OA has been correlated with the severity of lesions seen in radiographic imaging [73]. Also, studies have correlated the development of OA and lumbar disc degeneration with polymorphisms in the

Anti-inflammatory cytokines also present a role in the maintenance of OA. IL-4 is associated with chondroprotective effects as it is shown to reduce MMP production and, consequently, inhibit the degradation of proteoglycans in the articular cartilage [76]. However, chondrocytes from OA joints have shown a decreased susceptibility to this IL-4 protective effect, leaving the cartilage unprotected, quickening the degeneration via the action of the proinflammatory cytokines cited above [77]. In addition, a polymorphism in the gene encoding IL-4 and its main receptor (IL-4Rα) could predetermine the development of OA in hand and knee joints [78, 79]. It was also further reported that, when compared with healthy patients, OA patients pres-

The activation of IL-4 depends on intracellular signal transduction by gradual phosphorylation of IL-4Rα, which leads to the expression of several proinflammatory genes [81]. IL-4 production is mainly determined by T cells, especially Th2, which are present in the cellular infiltrates observed in OA [37]. It was reported that IL-4 alone or in combination with IL-10 is able to reduce the production of diverse proinflammatory mediators, such as IL-1β, TNF-α receptors, IL-6, PGE2, and

Due to its anti-inflammatory features, IL-10 is another cytokine that presents chondroprotective effects, and it is linked to the release of IFN [62]. *In vitro* studies have shown increased proteoglycan and type II collagen syntheses after the administration of IL-10 in chondrocytes [62]. The protective effects that IL-10 exhibits are likely due to a stimulation of the synthesis of IL-1β antagonist and a tissue inhibition of MMP-1 (TIMP-1) [85]. Also, IL-10, as well as IL-4, reduces apoptotic events

IL-10 induces the expression of bone morphogenetic protein-2 and -6 (BMP2 and BMP6), which are related to chondrogenesis as they belong to TGF-β family [88]. Together with BMP production, IL-10 activates signaling pathways, such as NKX-3.2/SOX9, that induce the differentiation of mesenchymal stem cells into chondrocytes [89]. Also, by reducing the expression of TNF-α receptors, IL-10 is able to attenuate the effect of TNF-α on synovial fibroblasts. A decrease in COX-2

The secretion of IL-10 can be influenced by physical exercises. Patients with and without OA had synovial fluid and periarticular tissue harvested from their knee before, during, and after they underwent exercise practice for 3 hours. A significant increase in IL-10 levels was observed in these patients after the exercise. Although it is not clear what exact mechanism led to this result, this observation is

gene encoding IL-18 and its receptor (IL-18R) [74, 75].

ent an elevated level of soluble IL-4Rα (sIL-4Rα) [80].

in chondrocytes and production of MMP [86, 87].

production was also noted in the same study [90].

**28**

Chemokines comprise small proteins that act as chemoattractants to assist cells to migrate to injured tissue. Diverse chemokines have gained attention in the development of OA. Some of them including their receptors, such as IL-8, CCL5, CCL19, CCR1, CCR2, CCR3, and CCR5, may induce the production of MMP-3 by chondrocytes and increase the breakdown of cartilage matrix components, which trigger the onset of OA [60, 93]. However, some chemokines might present a protective role in OA, such as stromal cell-derived factor-1 (also called CXCL12), whose main function is to recruit mesenchymal stem cells to the injured area in order to promote tissue repair [94].

Several chemokines were reported to be overexpressed in OA, such as IL-8/ CXCL-8, GROα/CXCL-1, MCP-1/CCL-2, RANTES/CCL-5, MIP-1α/CCL-3, and MIP-1β/CCL-4. Some of these chemokines are stimulated by IL-1β, which is upregulated in OA, and they induce MMP production upon binding to their ligands, causing tissue degradation [93]. Levels of INF-γ-inducible protein 10 (IP-10), also called as CXCL-10, in plasma and synovial fluid have been correlated with radiographic knee OA. CX3CL1, a serum fractalkine, has also been reported to be significantly elevated in severe knee OA in a study that compared OA patients with healthy patients [95].

To support the role of macrophage in the inflammatory response observed in OA, MCP-1, also known as chemokine ligand-2 (CCL2), has been reported to recruit macrophages into adipose tissue and atherosclerotic lesions [96]. Also, MCP-1 levels in both serum and synovial fluid has been associated with selfreported pain and disability in patients who present knee OA [97]. In addition, it was observed that, in severe knee OA, the levels of macrophage-derived chemokine (MDC) and IP-10 in synovial fluid were elevated, while eotaxin levels, an eosinophil chemotactic protein, were lower when compared with healthy patients [98].

#### **3.3 Adipokines**

Adipokines have been associated with the incidence and severity of OA [99]. *In vitro* studies reported that the presence of adipokines, such as leptin, adiponectin, visfatin, and resistin, increases the production of inflammatory mediators and also induces chondrolysis [99]. Although the exact mechanism of how these cytokines derived from adipose tissue act on arthritic joints has not yet been elucidated, researchers have studied the role of fat pad as a local inflammation mediator in OA, particularly in knee OA due to the infrapatellar fat pad, which has proven to be infiltrated with macrophages, lymphocytes, and granulocytes [100]. These findings support the thought that obesity supports the development of OA more through biochemical pathways rather than biomechanical overload risks on a weight-bearing joint.

### **3.4 Lipid mediators**

The COX-2 enzyme is responsible for the production of lipid mediators, including PGE2 and leukotrienes, and it is also upregulated in OA joints. In addition, the overexpression of COX-2 in OA has been associated with the increased production of IL-1β, TNF, and IL-6 via toll-like receptor-4 (TLR-4) [101]. Besides assisting the production of MMPs and other functions already cited above, PGE2 is also involved in apoptosis and structural changes that characterize arthritic disease [102].

Leukotrienes have also been investigated for their role in OA. These mediators are converted from arachidonic acid, which also produces PGE2 via the activity of the enzyme phospholipase A2 [21]. Leukotrienes, mainly leukotriene B4 (LTB4), are present, to a lesser extent, in OA synovium, bone, and cartilage. Also, LTB4 has been reported to stimulate the production of IL-1β and TNF in arthritic synovium [103].

#### **4. Conclusions**

The cumulative evidences over the years have shown that increased expression of proinflammatory cytokines, in particular IL-1β, TNF, and IL-6, in cartilage as well as synovial fluid and membrane, has played a key role in the pathogenesis of OA. Inflammatory processes linked with immune responses have characterized OA as a complex disease and not as a simple age-related cartilage degeneration as it is thought to be. The understanding of individual roles of inflammatory mediators and their compounds is of utmost importance to target new therapies for OA, since the current options are elusive and may be noneffective, invasive, or even capable of presenting serious side effects. Due to advancements in molecular tools, the overall aim would be to dissect the role of each cytokine in the pathophysiology of OA and, together with drug delivery systems, to develop specific anticytokine therapy, given that inflammatory responses contribute substantially to OA maintenance.

#### **Conflict of interest**

The authors have no conflict of interest to declare.

#### **Author details**

José Fábio dos Santos Duarte Lana\* and Bruno Lima Rodrigues Institute of Bone and Cartilage, Indaiatuba, Sao Paulo, Brazil

\*Address all correspondence to: josefabiolana@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**31**

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

multicenter osteoarthritis study and the osteoarthritis initiative. Arthithis Rheumatism. 2014;**65**(2):355-362

[9] Solomon DH, Husni ME, Libby PA, Yeomans ND, Lincoff AM, Lüscher TF, et al. The risk of major NSAID toxicity with celecoxib, ibuprofen, or naproxen: A secondary analysis of the PRECISION trial. The American Journal of Medicine.

[10] Lee T, Lu N, Felson DT, Choi HK, Dalal DS, Zhang Y, et al. Use of nonsteroidal anti-inflammatory drugs correlates with the risk of venous thromboembolism in knee osteoarthritis

patients: a UK population-based case-control study. Rheumatology,

[11] Lana J, Weglein A, Sampson S, Vicente F, Huber S, Souza C, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. Journal of Stem Cells and Regenerative Medicine.

[12] Dallari D, Stagni C, Rani N, Sabbioni G, Pelotti P, Torricelli P, et al. Ultrasound-guided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis. The American

Journal of Sports Medicine.

[13] Centeno CJ, Al-Sayegh H, Bashir J, Goodyear SH, D Freeman M. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment

2016;**44**(3):664-671

2016;**55**(6):1099-1105

2016;**12**(2):69-78

[8] Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Annals of the Rheumatic Diseases. 1957;**16**(4):494-502

2017;**130**(12):1415-1422.e4

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

[1] Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;**12**(10):580-592

[3] Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis and Rheumatism. 2008;**58**(1):15-25

[4] Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: A systematic review and metaanalysis. Osteoarthritis and Cartilage.

[5] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nature Reviews Rheumatology.

[6] Mapp PI, Walsh DA, Bowyer J, Maciewicz RA. Effects of a metalloproteinase inhibitor on osteochondral angiogenesis,

chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis and Cartilage. 2010;**18**(4):593-600

[7] Sharma L, Cooke TD, Guermazi A, Roemer FW, Nevitt MC. Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: Findings from the

[2] Jonsson H, Olafsdottir S, Sigurdardottir S, Aspelund T, Eiriksdottir G, Sigurdsson S, et al. Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: Risk factors and factors associated with late life prevalence in the AGES-Reykjavik study. BMC Musculoskeletal Disorders.

**References**

2016;**17**(1):1-9

2010;**18**(1):24-33

2010;**6**(11):625-635

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

#### **References**

*Osteoarthritis Biomarkers and Treatments*

**4. Conclusions**

**Conflict of interest**

**Author details**

Leukotrienes have also been investigated for their role in OA. These mediators are converted from arachidonic acid, which also produces PGE2 via the activity of the enzyme phospholipase A2 [21]. Leukotrienes, mainly leukotriene B4 (LTB4), are present, to a lesser extent, in OA synovium, bone, and cartilage. Also, LTB4 has been reported to stimulate the production of IL-1β and TNF in arthritic synovium [103].

The cumulative evidences over the years have shown that increased expression of proinflammatory cytokines, in particular IL-1β, TNF, and IL-6, in cartilage as well as synovial fluid and membrane, has played a key role in the pathogenesis of OA. Inflammatory processes linked with immune responses have characterized OA as a complex disease and not as a simple age-related cartilage degeneration as it is thought to be. The understanding of individual roles of inflammatory mediators and their compounds is of utmost importance to target new therapies for OA, since the current options are elusive and may be noneffective, invasive, or even capable of presenting serious side effects. Due to advancements in molecular tools, the overall aim would be to dissect the role of each cytokine in the pathophysiology of OA and, together with drug delivery systems, to develop specific anticytokine therapy, given

that inflammatory responses contribute substantially to OA maintenance.

The authors have no conflict of interest to declare.

José Fábio dos Santos Duarte Lana\* and Bruno Lima Rodrigues Institute of Bone and Cartilage, Indaiatuba, Sao Paulo, Brazil

\*Address all correspondence to: josefabiolana@gmail.com

**30**

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nature Reviews Rheumatology. 2016;**12**(10):580-592

[2] Jonsson H, Olafsdottir S, Sigurdardottir S, Aspelund T, Eiriksdottir G, Sigurdsson S, et al. Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: Risk factors and factors associated with late life prevalence in the AGES-Reykjavik study. BMC Musculoskeletal Disorders. 2016;**17**(1):1-9

[3] Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis and Rheumatism. 2008;**58**(1):15-25

[4] Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: A systematic review and metaanalysis. Osteoarthritis and Cartilage. 2010;**18**(1):24-33

[5] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nature Reviews Rheumatology. 2010;**6**(11):625-635

[6] Mapp PI, Walsh DA, Bowyer J, Maciewicz RA. Effects of a metalloproteinase inhibitor on osteochondral angiogenesis, chondropathy and pain behavior in a rat model of osteoarthritis. Osteoarthritis and Cartilage. 2010;**18**(4):593-600

[7] Sharma L, Cooke TD, Guermazi A, Roemer FW, Nevitt MC. Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: Findings from the

multicenter osteoarthritis study and the osteoarthritis initiative. Arthithis Rheumatism. 2014;**65**(2):355-362

[8] Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Annals of the Rheumatic Diseases. 1957;**16**(4):494-502

[9] Solomon DH, Husni ME, Libby PA, Yeomans ND, Lincoff AM, Lüscher TF, et al. The risk of major NSAID toxicity with celecoxib, ibuprofen, or naproxen: A secondary analysis of the PRECISION trial. The American Journal of Medicine. 2017;**130**(12):1415-1422.e4

[10] Lee T, Lu N, Felson DT, Choi HK, Dalal DS, Zhang Y, et al. Use of nonsteroidal anti-inflammatory drugs correlates with the risk of venous thromboembolism in knee osteoarthritis patients: a UK population-based case-control study. Rheumatology, 2016;**55**(6):1099-1105

[11] Lana J, Weglein A, Sampson S, Vicente F, Huber S, Souza C, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. Journal of Stem Cells and Regenerative Medicine. 2016;**12**(2):69-78

[12] Dallari D, Stagni C, Rani N, Sabbioni G, Pelotti P, Torricelli P, et al. Ultrasound-guided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis. The American Journal of Sports Medicine. 2016;**44**(3):664-671

[13] Centeno CJ, Al-Sayegh H, Bashir J, Goodyear SH, D Freeman M. A prospective multi-site registry study of a specific protocol of autologous bone marrow concentrate for the treatment

of shoulder rotator cuff tears and osteoarthritis. Journal of Pain Research. 2015;**8**:269-276

[14] Jo C, Lee Y, Shin W, Kim H, Chai J, Jeong E, et al. Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the of the Knee: A Proof-of-Concept Clinical Trial CHRIS. Stem cells. 2014;**32**(5):1254-1266

[15] Zheng S, Hunter DJ, Xu J, Ding C. Monoclonal antibodies for the treatment of osteoarthritis. Expert Opinion on Biological Therapy. 2016;**16**(12):1529-1540

[16] Chiusaroli R, Visentini M, Galimberti C, Casseler C, Mennuni L, Covaceuszach S, et al. Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis. Osteoarthritis and Cartilage [Internet]. 2013;**21**(11):1807-1810. DOI: 10.1016/j. joca.2013.08.015

[17] Ma CH, Lv Q, Yu YX, Zhang Y, Kong D, Niu KR, et al. Protective effects of tumor necrosis factor—A blockade by adalimumab on articular cartilage and subchondral bone in a rat model of osteoarthritis. Brazilian Journal of Medical and Biological Research. 2015;**48**:863-870

[18] Cohen SB, Proudman S, Kivitz AJ, Burch FX, Donohue JP, Burstein D, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Research & Therapy [Internet]. 2011;**13**(4):R125. Available from: http:// arthritis-research.biomedcentral.com/ articles/10.1186/ar3430

[19] Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism. 2013;**64**(6):1697-1707

[20] Haseeb A, Haqqi TM. Immunopathogenesis of osteoarthritis. Clinical Immunology. 2009;**6**(3):247-253

[21] Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: Latest findings and interpretations. Therapeutic Advances in Musculoskeletal Disease. 2013;**5**(2):77-94

[22] Orlowsky EW, Kraus VB. The role of innate immunity in osteoarthritis: When our first line of defense goes on the offensive. The Journal of Rheumatology. 2015;**42**(3):363-371

[23] Kandahari AM, Yang X, Dighe AS, Pan D, Cui Q. Recognition of immune response for the early diagnosis and treatment of osteoarthritis. Journal of Immunology Reseach. 2015;**2015**(192415):1-13

[24] Pessler F, Dai L, Diaz-Torne C, Gomez-Vaquero C, Paessler ME, Zheng DH, et al. The synovitis of "non-inflammatory" orthopaedic arthropathies: A quantitative histological and immunohistochemical analysis. Annals of the Rheumatic Diseases. 2008;**67**(8):1184-1187

[25] Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Research & Therapy. 2006;**8**(6):1-12

[26] Van Lent PLEM, Blom AB, Van Der Kraan P, Holthuysen AEM, Vitters E, Van Rooijen N, et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor?—Mediated osteophyte formation. Arthritis and Rheumatism. 2004;**50**(1):103-111

[27] Huss RS, Huddleston JI, Goodman SB, Butcher EC, Zabel BA. Synovial tissue-infiltrating natural killer cells

**33**

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

http://www.liebertonline.com/doi/ abs/10.1089/107999000414826

[35] Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthysz P. Accelerated collageninduced arthritis in IFN-y receptordeficient mice. Journal of Immunology.

1997 Jun 1;**158**(11):5507-5513

[36] Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen M, et al. Identification of a central role for complement in osteoarthritis. Nature Medicine. 2012;**17**(12):1674-1679

[37] Ishii H, Tanaka H, Katoh K, Nakamura H, Nagashima M, Yoshino S. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis and Cartilage. 2002;**10**(4):277-281

[38] Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P, et al. T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clinical and Diagnostic Laboratory Immunology.

[39] Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature Reviews Rheumatology.

[40] Saklatvala J. Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7-13;**322**(6079):547-549

[41] Chadjichristos C, Ghayor C, Kypriotou M, Martin G, Renard E, Ala-Kokko L, et al. Sp1 and Sp3 transcription

factors mediate interleukin-1β down-regulation of human type II collagen gene expression in articular chondrocytes. The Journal of Biological Chemistry. 2003;**278**(41):39762-39772

1998;**5**(4):430-437

2011;**7**(1):33-42

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

in osteoarthritis and peri-prosthetic

Rheumatism. 2011;**62**(12):3799-3805

[28] Xiaoqiang E, Yang C, Hongxue M, Yuebin Q, Guangye D, Jun X, Bi Z. Dendritic cells of synovium in experimental model of osteoarthritis of rabbits. Cellular Physiology and Biochemistry. 2012;**30**(1):23-32

inflammation. Arthritis and

[29] Dalbeth N, Callan MFC. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis and Rheumatism.

[30] Sower LE, Klimpel GR, Hanna W, Froelich CJ. Extracellular activities of human granzymes. Cellular Immunology [Internet]. 1996;**171**(1):159-163. Available from: http://www.ncbi.nlm.nih.gov/

[31] Froelich CJ, Dixit VM, Yang X. Lymphocyte granule-mediated apoptosis: Matters of viral mimicry and deadly proteases. Immunology Today.

[32] Tak PP, Spaeny-Dekking L, Kraan MC, Breedveld FC, Froelich CJ, Hack CE. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clinical and Experimental Immunology.

[33] Fox SW, Chambers TJ. Interferon-γ directly inhibits TRANCE-induced osteoclastogenesis. Biochemical and Biophysical Research Communications.

[34] Madyastha PR, Yang S, Ries WL, Key LL. IFN-γ enhances osteoclast generation in cultures of peripheral blood from Osteopetrotic patients and normalizes superoxide production. Journal of Interferon & Cytokine Research [Internet]. 2000;**20**(7):645-652. Available from:

2002;**46**(7):1763-1772

pubmed/8660852

1998;**19**(1):30-36

1999;**116**:366-370

2000;**276**(3):868-872

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

in osteoarthritis and peri-prosthetic inflammation. Arthritis and Rheumatism. 2011;**62**(12):3799-3805

*Osteoarthritis Biomarkers and Treatments*

of shoulder rotator cuff tears and osteoarthritis. Journal of Pain Research. [20] Haseeb A, Haqqi TM.

Immunopathogenesis of osteoarthritis. Clinical Immunology. 2009;**6**(3):247-253

[22] Orlowsky EW, Kraus VB. The role of innate immunity in osteoarthritis: When our first line of defense goes on

the offensive. The Journal of Rheumatology. 2015;**42**(3):363-371

[23] Kandahari AM, Yang X, Dighe AS, Pan D, Cui Q. Recognition of immune response for the early diagnosis

and treatment of osteoarthritis. Journal of Immunology Reseach.

[24] Pessler F, Dai L, Diaz-Torne C, Gomez-Vaquero C, Paessler ME, Zheng DH, et al. The synovitis of "non-inflammatory" orthopaedic arthropathies: A quantitative

histological and immunohistochemical analysis. Annals of the Rheumatic Diseases. 2008;**67**(8):1184-1187

destructive and inflammatory responses in osteoarthritis. Arthritis Research &

[26] Van Lent PLEM, Blom AB, Van Der Kraan P, Holthuysen AEM, Vitters E, Van Rooijen N, et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor?—Mediated osteophyte formation. Arthritis and Rheumatism.

[27] Huss RS, Huddleston JI, Goodman SB, Butcher EC, Zabel BA. Synovial tissue-infiltrating natural killer cells

[25] Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE. The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other

Therapy. 2006;**8**(6):1-12

2004;**50**(1):103-111

2015;**2015**(192415):1-13

[21] Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: Latest findings and interpretations. Therapeutic Advances in Musculoskeletal Disease. 2013;**5**(2):77-94

[14] Jo C, Lee Y, Shin W, Kim H, Chai J, Jeong E, et al. Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the of the Knee: A Proof-of-Concept Clinical Trial CHRIS. Stem cells.

[15] Zheng S, Hunter DJ, Xu J, Ding C. Monoclonal antibodies for the treatment of osteoarthritis. Expert Opinion on Biological Therapy.

2015;**8**:269-276

2014;**32**(5):1254-1266

2016;**16**(12):1529-1540

joca.2013.08.015

2015;**48**:863-870

articles/10.1186/ar3430

[16] Chiusaroli R, Visentini M, Galimberti C, Casseler C, Mennuni L, Covaceuszach S, et al. Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis.

Osteoarthritis and Cartilage [Internet]. 2013;**21**(11):1807-1810. DOI: 10.1016/j.

[17] Ma CH, Lv Q, Yu YX, Zhang Y, Kong D, Niu KR, et al. Protective effects of tumor necrosis factor—A blockade by adalimumab on articular cartilage and subchondral bone in a rat model of osteoarthritis. Brazilian Journal of Medical and Biological Research.

[18] Cohen SB, Proudman S, Kivitz AJ, Burch FX, Donohue JP, Burstein D, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Research & Therapy [Internet]. 2011;**13**(4):R125. Available from: http:// arthritis-research.biomedcentral.com/

[19] Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: A disease of the joint as an organ. Arthritis and Rheumatism. 2013;**64**(6):1697-1707

**32**

[28] Xiaoqiang E, Yang C, Hongxue M, Yuebin Q, Guangye D, Jun X, Bi Z. Dendritic cells of synovium in experimental model of osteoarthritis of rabbits. Cellular Physiology and Biochemistry. 2012;**30**(1):23-32

[29] Dalbeth N, Callan MFC. A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis and Rheumatism. 2002;**46**(7):1763-1772

[30] Sower LE, Klimpel GR, Hanna W, Froelich CJ. Extracellular activities of human granzymes. Cellular Immunology [Internet]. 1996;**171**(1):159-163. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/8660852

[31] Froelich CJ, Dixit VM, Yang X. Lymphocyte granule-mediated apoptosis: Matters of viral mimicry and deadly proteases. Immunology Today. 1998;**19**(1):30-36

[32] Tak PP, Spaeny-Dekking L, Kraan MC, Breedveld FC, Froelich CJ, Hack CE. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clinical and Experimental Immunology. 1999;**116**:366-370

[33] Fox SW, Chambers TJ. Interferon-γ directly inhibits TRANCE-induced osteoclastogenesis. Biochemical and Biophysical Research Communications. 2000;**276**(3):868-872

[34] Madyastha PR, Yang S, Ries WL, Key LL. IFN-γ enhances osteoclast generation in cultures of peripheral blood from Osteopetrotic patients and normalizes superoxide production. Journal of Interferon & Cytokine Research [Internet]. 2000;**20**(7):645-652. Available from:

http://www.liebertonline.com/doi/ abs/10.1089/107999000414826

[35] Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Matthysz P. Accelerated collageninduced arthritis in IFN-y receptordeficient mice. Journal of Immunology. 1997 Jun 1;**158**(11):5507-5513

[36] Wang Q, Rozelle AL, Lepus CM, Scanzello CR, Song JJ, Larsen M, et al. Identification of a central role for complement in osteoarthritis. Nature Medicine. 2012;**17**(12):1674-1679

[37] Ishii H, Tanaka H, Katoh K, Nakamura H, Nagashima M, Yoshino S. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis and Cartilage. 2002;**10**(4):277-281

[38] Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P, et al. T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clinical and Diagnostic Laboratory Immunology. 1998;**5**(4):430-437

[39] Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nature Reviews Rheumatology. 2011;**7**(1):33-42

[40] Saklatvala J. Tumour necrosis factor α stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7-13;**322**(6079):547-549

[41] Chadjichristos C, Ghayor C, Kypriotou M, Martin G, Renard E, Ala-Kokko L, et al. Sp1 and Sp3 transcription factors mediate interleukin-1β down-regulation of human type II collagen gene expression in articular chondrocytes. The Journal of Biological Chemistry. 2003;**278**(41):39762-39772

[42] Shlopov BV, Gumanovskaya ML, Hasty KA. Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis and Rheumatism. 2000;**43**(1):195-205

[43] Fan Z, Bau B, Yang H, Soeder S, Aigner T. Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin-1? Arthritis and Rheumatism. 2005;**52**(1):136-143

[44] Cortial D, Gouttenoire J, Rousseau CF, Ronzière MC, Piccardi N, Msika P, et al. Activation by IL-1 of bovine articular chondrocytes in culture within a 3D collagen-based scaffold. An in vitro model to address the effect of compounds with therapeutic potential in osteoarthritis. Osteoarthritis and Cartilage. 2006;**14**(7):631-640

[45] Silvestri T, Pulsatelli L, Dolzani P, Frizziero L, Facchini A, Meliconi R. In vivo expression of inflammatory cytokine receptors in the joint compartments of patients with arthritis. Rheumatology International. 2006;**26**(4):360-368

[46] Roman-Blas JA, Jimenez SA. NF-κB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis and Cartilage. 2006;**14**(9):839-848

[47] Kobayashi T, Notoya K, Naito T, Unno S, Nakamura A, Martel-Pelletier J, et al. Pioglitazone, a peroxisome proliferator-activated receptor γ agonist, reduces the progression of experimental osteoarthritis in Guinea pigs. Arthritis and Rheumatism. 2005;**52**(2):479-487

[48] Boileau C, Martel-Pelletier J, Fahmi H, Mineau F, Boily M, Pelletier JP. The peroxisome proliferator-activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model

of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways. Arthritis and Rheumatism. 2007;**56**(7):2288-2298

[49] Wang P, Zhu F, Konstantopoulos K. Prostaglandin E 2 induces interleukin-6 expression in human chondrocytes via cAMP/protein kinase A- and phosphatidylinositol 3-kinasedependent NF-κB activation. American Journal of Physiology. Cell Physiology. 2010;**298**:1445-1456

[50] Stannus O, Jones G, Cicuttini F, Parameswaran V, Quinn S, Burgess J, et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis and Cartilage. 2010;**18**(11):1441-1447

[51] Sui Y, Lee JH, DiMicco MA, Vanderploeg EJ, Blake SM, Hung HH, et al. Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor α in immature bovine and adult human articular cartilage. Arthritis and Rheumatism. 2009;**60**(10):2985-2996

[52] Rowan AD, Koshy PJT, Shingleton WD, Degnan BA, Heath JK, Vernallis AB, et al. Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis and Rheumatism. 2001;**44**(7):1620-1632

[53] de Hooge ASK, van de Loo FAJ, Bennink MB, Arntz OJ, de Hooge P, van den Berg WB. Male IL-6 gene knockout mice developed more advanced osteoarthritis upon aging. Osteoarthritis and Cartilage. 2005;**13**(1):66-73

[54] van de Loo FA, Kuiper S, van Enckevort FH, Arntz OJ, van den Berg WB. Interleukin-6 reduces cartilage destruction during experimental

**35**

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

in patients with knee osteoarthritis. Disease Markers. 2013;**35**(3):203-206

[62] Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The role of

cytokines in the pathogenesis of osteoarthritis. Mediators of Inflammation. 2014;**2014**:561459

inflammatory and anti-inflammatory

[63] Noordenbos T, Yeremenko N, Gofita I, Van De Sande M, Tak PP, Caňete JD, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis and Rheumatism. 2012;**64**(1):99-109

[64] Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis and Cartilage.

[65] Lubberts E, Joosten LAB, Van De Loo FAJ, Van Den Bersselaar LAM, Van Den Berg WB. Reduction of interleukin-17-induced inhibition of chondrocyte proteoglycan synthesis in intact murine articular cartilage by interleukin-4.

Arthritis and Rheumatism. 2000;**43**(6):1300-1306

2014;**42**(1):138-144

Gene. 2014;**533**(1):119-122

2007;**48**(5):239-245

[66] Chen B, Deng Y, Tan Y, Qin J, Bin CL. Association between severity of knee osteoarthritis and serum and synovial fluid interleukin 17 concentrations. The Journal of International Medical Research.

[67] Han L, Lee HS, Yoon JH, Choi WS, Park YG, Nam SW, et al. Association of IL-17A and IL-17F single nucleotide polymorphisms with susceptibility to osteoarthritis in a Korean population.

[68] Honorati MC, Cattini L, Facchini A. VEGF production by osteoarthritic chondrocytes cultured in micromass and stimulated by IL-17 and TNFα. Connective Tissue Research.

2006;**14**(4):345-352

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

arthritis. A study in interleukin-6 deficient mice. The American Journal of

[55] Steeve KT, Marc P, Sandrine T, Dominique H, Yannick F. IL-6, RANKL, TNF-alpha/IL-1: Interrelations in bone resorption pathophysiology. Cytokine & Growth Factor Reviews.

[56] Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, et al. Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identity two subgroups of osteoarthritic patients. Osteoarthritis and Cartilage.

[57] Sakao K, Takahashi KA, Arai Y, Saito M, Honjo K, Hiraoka N, et al. Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis. Journal of Bone and Mineral Metabolism. 2009;**27**(4):412-423

[58] Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, et al. Targeting interleukin-15 in patients with rheumatoid arthritis: A proof-of-concept study. Arthritis and Rheumatism. 2005;**52**(9):2686-2692

[59] Waldmann TA, Tagaya Y. The multifaceted regulation of Interleukin-15 expression and the role of this cytokine in Nk cell differentiation and host response to intracellular pathogens. Annual Review of Immunology. 1999;**17**(1):19-49

[60] Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2013;**51**(2):249-257

[61] Sun J-M, Sun L-Z, Liu J, Su B, Shi L. Serum Interleukin-15 levels are associated with severity of pain

Pathology. 1997;**151**(1):177-191

2004;**15**(1):49-60

2002;**10**(6):491-500

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

arthritis. A study in interleukin-6 deficient mice. The American Journal of Pathology. 1997;**151**(1):177-191

*Osteoarthritis Biomarkers and Treatments*

[42] Shlopov BV, Gumanovskaya ML, Hasty KA. Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis. Arthritis and Rheumatism. 2000;**43**(1):195-205

of osteoarthritis: In vivo protective effects mediated through the inhibition

pathways. Arthritis and Rheumatism.

[49] Wang P, Zhu F, Konstantopoulos

[50] Stannus O, Jones G, Cicuttini F, Parameswaran V, Quinn S, Burgess J, et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthritis and Cartilage.

of key signaling and catabolic

K. Prostaglandin E 2 induces interleukin-6 expression in human chondrocytes via cAMP/protein kinase A- and phosphatidylinositol 3-kinasedependent NF-κB activation. American Journal of Physiology. Cell Physiology.

2007;**56**(7):2288-2298

2010;**298**:1445-1456

2010;**18**(11):1441-1447

[51] Sui Y, Lee JH, DiMicco MA, Vanderploeg EJ, Blake SM, Hung HH, et al. Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor α in immature bovine and adult human articular cartilage. Arthritis and Rheumatism. 2009;**60**(10):2985-2996

[52] Rowan AD, Koshy PJT, Shingleton WD, Degnan BA, Heath JK, Vernallis AB, et al. Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis and Rheumatism. 2001;**44**(7):1620-1632

[53] de Hooge ASK, van de Loo FAJ, Bennink MB, Arntz OJ, de Hooge P, van den Berg WB. Male IL-6 gene knockout

osteoarthritis upon aging. Osteoarthritis

mice developed more advanced

and Cartilage. 2005;**13**(1):66-73

[54] van de Loo FA, Kuiper S, van Enckevort FH, Arntz OJ, van den Berg WB. Interleukin-6 reduces cartilage destruction during experimental

[43] Fan Z, Bau B, Yang H, Soeder S, Aigner T. Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin-1? Arthritis and Rheumatism. 2005;**52**(1):136-143

[44] Cortial D, Gouttenoire J, Rousseau CF, Ronzière MC, Piccardi N, Msika P, et al. Activation by IL-1 of bovine articular chondrocytes in culture within a 3D collagen-based scaffold. An in vitro model to address the effect of compounds with therapeutic potential in osteoarthritis. Osteoarthritis and Cartilage. 2006;**14**(7):631-640

[45] Silvestri T, Pulsatelli L, Dolzani P, Frizziero L, Facchini A, Meliconi R. In vivo expression of inflammatory cytokine receptors in the joint compartments of patients with

arthritis. Rheumatology International.

[46] Roman-Blas JA, Jimenez SA. NF-κB

as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis and Cartilage.

[47] Kobayashi T, Notoya K, Naito T, Unno S, Nakamura A, Martel-Pelletier J, et al. Pioglitazone, a peroxisome proliferator-activated receptor γ agonist, reduces the progression of experimental osteoarthritis in Guinea pigs. Arthritis and Rheumatism.

[48] Boileau C, Martel-Pelletier J, Fahmi H, Mineau F, Boily M, Pelletier JP. The peroxisome proliferator-activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model

2006;**26**(4):360-368

2006;**14**(9):839-848

2005;**52**(2):479-487

**34**

[55] Steeve KT, Marc P, Sandrine T, Dominique H, Yannick F. IL-6, RANKL, TNF-alpha/IL-1: Interrelations in bone resorption pathophysiology. Cytokine & Growth Factor Reviews. 2004;**15**(1):49-60

[56] Massicotte F, Lajeunesse D, Benderdour M, Pelletier JP, Hilal G, Duval N, et al. Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identity two subgroups of osteoarthritic patients. Osteoarthritis and Cartilage. 2002;**10**(6):491-500

[57] Sakao K, Takahashi KA, Arai Y, Saito M, Honjo K, Hiraoka N, et al. Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis. Journal of Bone and Mineral Metabolism. 2009;**27**(4):412-423

[58] Baslund B, Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, et al. Targeting interleukin-15 in patients with rheumatoid arthritis: A proof-of-concept study. Arthritis and Rheumatism. 2005;**52**(9):2686-2692

[59] Waldmann TA, Tagaya Y. The multifaceted regulation of Interleukin-15 expression and the role of this cytokine in Nk cell differentiation and host response to intracellular pathogens. Annual Review of Immunology. 1999;**17**(1):19-49

[60] Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone. 2013;**51**(2):249-257

[61] Sun J-M, Sun L-Z, Liu J, Su B, Shi L. Serum Interleukin-15 levels are associated with severity of pain in patients with knee osteoarthritis. Disease Markers. 2013;**35**(3):203-206

[62] Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators of Inflammation. 2014;**2014**:561459

[63] Noordenbos T, Yeremenko N, Gofita I, Van De Sande M, Tak PP, Caňete JD, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis and Rheumatism. 2012;**64**(1):99-109

[64] Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis and Cartilage. 2006;**14**(4):345-352

[65] Lubberts E, Joosten LAB, Van De Loo FAJ, Van Den Bersselaar LAM, Van Den Berg WB. Reduction of interleukin-17-induced inhibition of chondrocyte proteoglycan synthesis in intact murine articular cartilage by interleukin-4. Arthritis and Rheumatism. 2000;**43**(6):1300-1306

[66] Chen B, Deng Y, Tan Y, Qin J, Bin CL. Association between severity of knee osteoarthritis and serum and synovial fluid interleukin 17 concentrations. The Journal of International Medical Research. 2014;**42**(1):138-144

[67] Han L, Lee HS, Yoon JH, Choi WS, Park YG, Nam SW, et al. Association of IL-17A and IL-17F single nucleotide polymorphisms with susceptibility to osteoarthritis in a Korean population. Gene. 2014;**533**(1):119-122

[68] Honorati MC, Cattini L, Facchini A. VEGF production by osteoarthritic chondrocytes cultured in micromass and stimulated by IL-17 and TNFα. Connective Tissue Research. 2007;**48**(5):239-245

[69] Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. Journal of Immunology. 1999;**162**(2):1096-1100

[70] Dai SM, Shan ZZ, Nishioka K, Yudoh K. Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: Direct effect on chondrocytes may not be pivotal. Annals of the Rheumatic Diseases. 2005;**64**(5):735-742

[71] Joosten LAB, Smeets RL, Koenders MI, Van Den Bersselaar LAM, Helsen MMA, Oppers-Walgreen B, et al. Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction. The American Journal of Pathology. 2004;**165**(3):959-967

[72] John T, Kohl B, Mobasheri a EW, Shakibaei M. Interleukin-18 induces apoptosis in human articular chondrocytes. Histology and Histopathology. 2007;**22**(5):469-482

[73] Wang Y, Xu D, Long L, Deng X, Tao R, Huang G. Correlation between plasma, synovial fluid and articular cartilage Interleukin-18 with radiographic severity in 33 patients with osteoarthritis of the knee. Clinical and Experimental Medicine. 2014;**14**(3):297-304

[74] Hulin-Curtis SL, Bidwell JL, Perry MJ. Evaluation of IL18 and IL18R1 polymorphisms: Genetic susceptibility to knee osteoarthritis. International Journal of Immunogenetics. 2012;**39**(2):106-109

[75] Omair A. An association study of interleukin 18 receptor genes (IL18R1 and IL18RAP) in lumbar disc degeneration. Open Orthopaedics Journal. 2012;**6**(1):164-171

[76] Van Lent PLEM, Holthuysen AEM, Slöetjes A, Lubberts E, Van Den Berg WB. Local overexpression of adenoviral IL-4 protects cartilage from metalloproteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs. Osteoarthritis and Cartilage. 2002;**10**(3):234-243

[77] Millward-Sadler SJ, Wright MO, Davies LW, Nuki G, Salter DM. Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Arthritis and Rheumatism. 2000;**43**(9):2091-2099

[78] Vargiolu M, Silvestri T, Bonora E, Dolzani P, Pulsatelli L, Addimanda O, et al. Interleukin-4/interleukin-4 receptor gene polymorphisms in hand osteoarthritis. Osteoarthritis and Cartilage. 2010;**18**(6):810-816

[79] Yigit S, Inanir A, Tekcan A, Tural E, Ozturk GT, Kismali G, et al. Significant association of interleukin-4 gene intron 3 VNTR polymorphism with susceptibility to knee osteoarthritis. Gene. 2014;**537**(1):6-9

[80] Silvestri T, Pulsatelli L, Dolzani P, Facchini A, Meliconi R. Elevated serum levels of soluble interleukin-4 receptor in osteoarthritis. Osteoarthritis and Cartilage. 2006;**14**(7):717-719

[81] Bhattacharjee A, Shukla M, Yakubenko VP, Mulya A, Kundu S, Cathcart MK. IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages. Free Radical Biology & Medicine. 2013;**54**(216):1-16

[82] Van Meegeren MER, Roosendaal G, Jansen NWD, Wenting MJG, Van Wesel ACW, Van Roon JAG, et al. IL-4 alone and in combination with IL-10

**37**

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers*

somitic chondrogenesis. Genes & Development. 2002;**16**(15):1990-2005

[90] Alaaeddine N, Di Battista JA, Pelletier JP, Kiansa K, Cloutier JM, Martel-Pelletier J. Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the anti-inflammatory cytokines interleukin-4, interleukin- 10, and interleukin-13 in osteoarthritic synovial fibroblasts: Distinct targeting in the signaling pathways. Arthritis and Rheumatism. 1999;**42**(4):710-718

[91] Helmark IC, Mikkelsen UR, Børglum J, Rothe A, Petersen MC, Andersen O, et al. Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: A randomized controlled trial. Arthritis Research & Therapy. 2010;**12**(4):R126

[92] Angele P, Yoo JU, Smith C, Mansour J, Jepsen KJ, Nerlich M, et al. Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor

cells differentiated in vitro. Journal of Orthopaedic Research.

[93] Borzí RM, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C

chemokines. Arthritis and Rheumatism.

Bhattacharyya BJ. CXCR4 signaling in the regulation of stem cell migration and development. Journal of Neuroimmunology.

[95] Zou Y, Li Y, Lu L, Lin Y, Liang W, Su Z, et al. Correlation of fractalkine concentrations in serum and synovial fluid with the radiographic severity of

2003;**21**(3):451-457

2000;**43**(8):1734-1741

2008;**198**(1-2):31-38

[94] Miller RJ, Banisadr G,

*DOI: http://dx.doi.org/10.5772/intechopen.82565*

protects against blood-induced cartilage damage. Osteoarthritis and Cartilage.

[84] Yorimitsu M, Nishida K, Shimizu A, Doi H, Miyazawa S, Komiyama T, et al. Intra-articular injection of interleukin-4 decreases nitric oxide production by chondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints. Osteoarthritis and Cartilage.

[85] Lacraz S, Nicod LP, Chicheportiche

[86] Wang Y, Lou S. Direct protective effect of interleukin-10 on articular chondrocytes in vitro. Chinese Medical

[87] John T, Müller RD, Oberholzer A, Zreiqat H, Kohl B, Ertel W, et al. Interleukin-10 modulates pro-apoptotic effects of TNF-α in human articular chondrocytes in vitro. Cytokine.

[88] Umulis D, O'Connor MB, Blair SS. The extracellular

2009;**136**(22):3715-3728

regulation of bone morphogenetic protein signaling. Development.

[89] Zeng L, Kempf H, Murtaugh LC, Sato ME, Lassar AB. Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce

Journal. 2001;**114**(7):723-725

R, Welgus HG, Dayer JM. IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes. The Journal of Clinical Investigation.

[83] Schuerwegh AJ, Dombrecht EJ, Stevens WJ, Van Offel JF, Bridts CH, De Clerck LS. Influence of proinflammatory (IL-1α, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis and Cartilage.

2012;**20**(7):764-772

2003;**11**(9):681-687

2008;**16**(7):764-771

1995;**96**(5):2304-2310

2007;**40**(3):226-234

*Osteoarthritis as a Chronic Inflammatory Disease: A Review of the Inflammatory Markers DOI: http://dx.doi.org/10.5772/intechopen.82565*

protects against blood-induced cartilage damage. Osteoarthritis and Cartilage. 2012;**20**(7):764-772

*Osteoarthritis Biomarkers and Treatments*

[69] Olee T, Hashimoto S, Quach J, Lotz M. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. Journal of Immunology.

[76] Van Lent PLEM, Holthuysen AEM, Slöetjes A, Lubberts E, Van Den Berg WB. Local overexpression of adenoviral IL-4 protects cartilage from metalloproteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs. Osteoarthritis and Cartilage.

[77] Millward-Sadler SJ, Wright MO,

metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Arthritis and Rheumatism. 2000;**43**(9):2091-2099

[78] Vargiolu M, Silvestri T, Bonora E, Dolzani P, Pulsatelli L, Addimanda O, et al. Interleukin-4/interleukin-4 receptor gene polymorphisms in hand osteoarthritis. Osteoarthritis and Cartilage. 2010;**18**(6):810-816

[79] Yigit S, Inanir A, Tekcan A, Tural E, Ozturk GT, Kismali G, et al. Significant association of interleukin-4 gene intron 3 VNTR polymorphism with susceptibility to knee osteoarthritis.

[80] Silvestri T, Pulsatelli L, Dolzani P, Facchini A, Meliconi R. Elevated serum levels of soluble interleukin-4 receptor in osteoarthritis. Osteoarthritis and Cartilage. 2006;**14**(7):717-719

[81] Bhattacharjee A, Shukla M, Yakubenko VP, Mulya A, Kundu S, Cathcart MK. IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages. Free Radical Biology & Medicine.

[82] Van Meegeren MER, Roosendaal G, Jansen NWD, Wenting MJG, Van Wesel ACW, Van Roon JAG, et al. IL-4 alone and in combination with IL-10

Gene. 2014;**537**(1):6-9

2013;**54**(216):1-16

2002;**10**(3):234-243

Davies LW, Nuki G, Salter DM. Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix

[70] Dai SM, Shan ZZ, Nishioka K, Yudoh K. Implication of interleukin

chondrocytes in arthritis: Direct effect on chondrocytes may not be pivotal. Annals of the Rheumatic Diseases.

[71] Joosten LAB, Smeets RL, Koenders

MI, Van Den Bersselaar LAM, Helsen MMA, Oppers-Walgreen B, et al. Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction. The American Journal of Pathology.

[72] John T, Kohl B, Mobasheri a EW, Shakibaei M. Interleukin-18 induces apoptosis in human articular

[73] Wang Y, Xu D, Long L, Deng X, Tao R, Huang G. Correlation between plasma, synovial fluid and articular cartilage Interleukin-18 with radiographic severity in 33 patients with osteoarthritis of the knee. Clinical and Experimental Medicine.

[74] Hulin-Curtis SL, Bidwell JL, Perry MJ. Evaluation of IL18 and IL18R1 polymorphisms: Genetic susceptibility to knee osteoarthritis. International

Journal of Immunogenetics.

Journal. 2012;**6**(1):164-171

[75] Omair A. An association study of interleukin 18 receptor genes (IL18R1 and IL18RAP) in lumbar disc degeneration. Open Orthopaedics

1999;**162**(2):1096-1100

18 in production of matrix metalloproteinases in articular

2005;**64**(5):735-742

2004;**165**(3):959-967

chondrocytes. Histology and Histopathology. 2007;**22**(5):469-482

2014;**14**(3):297-304

2012;**39**(2):106-109

**36**

[83] Schuerwegh AJ, Dombrecht EJ, Stevens WJ, Van Offel JF, Bridts CH, De Clerck LS. Influence of proinflammatory (IL-1α, IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis and Cartilage. 2003;**11**(9):681-687

[84] Yorimitsu M, Nishida K, Shimizu A, Doi H, Miyazawa S, Komiyama T, et al. Intra-articular injection of interleukin-4 decreases nitric oxide production by chondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints. Osteoarthritis and Cartilage. 2008;**16**(7):764-771

[85] Lacraz S, Nicod LP, Chicheportiche R, Welgus HG, Dayer JM. IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes. The Journal of Clinical Investigation. 1995;**96**(5):2304-2310

[86] Wang Y, Lou S. Direct protective effect of interleukin-10 on articular chondrocytes in vitro. Chinese Medical Journal. 2001;**114**(7):723-725

[87] John T, Müller RD, Oberholzer A, Zreiqat H, Kohl B, Ertel W, et al. Interleukin-10 modulates pro-apoptotic effects of TNF-α in human articular chondrocytes in vitro. Cytokine. 2007;**40**(3):226-234

[88] Umulis D, O'Connor MB, Blair SS. The extracellular regulation of bone morphogenetic protein signaling. Development. 2009;**136**(22):3715-3728

[89] Zeng L, Kempf H, Murtaugh LC, Sato ME, Lassar AB. Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis. Genes & Development. 2002;**16**(15):1990-2005

[90] Alaaeddine N, Di Battista JA, Pelletier JP, Kiansa K, Cloutier JM, Martel-Pelletier J. Inhibition of tumor necrosis factor alpha-induced prostaglandin E2 production by the anti-inflammatory cytokines interleukin-4, interleukin- 10, and interleukin-13 in osteoarthritic synovial fibroblasts: Distinct targeting in the signaling pathways. Arthritis and Rheumatism. 1999;**42**(4):710-718

[91] Helmark IC, Mikkelsen UR, Børglum J, Rothe A, Petersen MC, Andersen O, et al. Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: A randomized controlled trial. Arthritis Research & Therapy. 2010;**12**(4):R126

[92] Angele P, Yoo JU, Smith C, Mansour J, Jepsen KJ, Nerlich M, et al. Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro. Journal of Orthopaedic Research. 2003;**21**(3):451-457

[93] Borzí RM, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines. Arthritis and Rheumatism. 2000;**43**(8):1734-1741

[94] Miller RJ, Banisadr G, Bhattacharyya BJ. CXCR4 signaling in the regulation of stem cell migration and development. Journal of Neuroimmunology. 2008;**198**(1-2):31-38

[95] Zou Y, Li Y, Lu L, Lin Y, Liang W, Su Z, et al. Correlation of fractalkine concentrations in serum and synovial fluid with the radiographic severity of knee osteoarthritis. Annals of Clinical Biochemistry. 2013;**50**(6):571-575

[96] Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. The Journal of Clinical Investigation. 2006;**116**(6):1494-1505

[97] Li L, Jiang BE. Serum and synovial fluid chemokine ligand 2/ monocyte chemoattractant protein 1 concentrations correlates with symptomatic severity in patients with knee osteoarthritis. Annals of Clinical Biochemistry. 2015;**52**(2):276-282

[98] Beekhuizen M, Gierman LM, van Spil WE, Van Osch GJVM, Huizinga TWJ, Saris DBF, et al. An explorative study comparing levels of soluble mediators in control and osteoarthritic synovial fluid. Osteoarthritis and Cartilage. 2013;**21**(7):918-922

[99] Conde J, Scotece M, Gómez R, Lopez V, Gómez-Reino JJ, Gualillo O. Adipokines and osteoarthritis: Novel molecules involved in the pathogenesis and progression of disease. Arthritis. 2011;**2011**:1-8

[100] Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJVM, Van Offel JF, Verhaar JAN, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: A narrative review. Osteoarthritis and Cartilage. 2010;**18**(7):876-882

[101] Geng Y, Blanco FJ, Cornelisson M, Lotz M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes. Journal of Immunology. 1995;**155**(2):796-801

[102] Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues.

Seminars in Arthritis and Rheumatism. 2003;**33**(3):155-167

[103] Oliveira SHP, Canetti C, Ribeiro RA, Cunha FQ. Neutrophil migration induced by IL-1β depends upon LTB4 released by macrophages and upon TNF-α and IL-1β released by mast cells. Inflammation. 2008;**31**(1):36-46

**39**

**Chapter 3**

**Abstract**

**1. Introduction**

classified into:

therapy, and infiltrative therapy.

and in some cases by arthroshaving [2].

Fat Tissue's Graft in Osteoarthritis

*Edoardo De Fenu, Berardino Di Paola, Marco Ruggiero,* 

Osteoarthritis (OA) represents one of the most common causes of joint pain and disability with related changes in bone morphology. In last years, this pathology is steadily increasing due to the continuous increase in the average life expectancy and the rate of active population. In recent years, there have been many conservative treatments for symptomatic gonarthrosis in order to reduce pain and delay or avoid the implantation of a knee prosthesis. The most studied and used was infiltrating treatment. Our group has been paying attention to regenerative medicine for many years, focusing on the characteristics of adipose tissue and the presence of multipotent mesenchymal cells, particularly in the vascular stromal area. Mesenchymal stem cells (MSCs) of adipose tissue can commit toward the chondrogenic, osteogenic, adipogenic, myogenic, and neurogenic lineages. Our group has continued the studies in this field by submitting this to treatment patients with grade II–III arthrosis according to the scale of Kellgren-Lawrence or patients with IV degree of such scale inoperable for internal reasons. To date, with a 4-year follow-up, our results are satisfactory in terms of pain reduction, improvement in

**Keywords:** osteoarthritis, fat tissue, joint, adipose stem cells, conservative treatment

Osteoarthritis is a common degenerative joint cartilage disorder associated with hypertrophic bone changes and loss of joint cartilage integrity [1]. It causes pain, stiffness, and reduction of the associated function, consequently, disability with relative difficulty for the patient in carrying out the normal daily activities [2]. Risk factors are represented by genetic factors, female sex, post-traumatic conditions, age, obesity, etc. [3–6]. Treatment is therefore aimed at reducing symptoms, improving quality of life, and preventing its progression. Treatment options can be

• Conservative treatment, such as lifestyle education, pain therapy and physio-

• Surgical treatment, traditionally represented by arthroplasty and osteotomy

*Bruno Carlesimo, Andrea Conversi and Ezio Adriani*

Treatment: Indications,

joint function, and recovery of daily and sports activities.

Preparations, and Results

### **Chapter 3**

*Osteoarthritis Biomarkers and Treatments*

knee osteoarthritis. Annals of Clinical Biochemistry. 2013;**50**(6):571-575

Seminars in Arthritis and Rheumatism.

[103] Oliveira SHP, Canetti C, Ribeiro RA, Cunha FQ. Neutrophil migration induced by IL-1β depends upon LTB4 released by macrophages and upon TNF-α and IL-1β released by mast cells. Inflammation. 2008;**31**(1):36-46

2003;**33**(3):155-167

[96] Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. The Journal of Clinical Investigation.

2006;**116**(6):1494-1505

[97] Li L, Jiang BE. Serum and synovial fluid chemokine ligand 2/ monocyte chemoattractant protein 1 concentrations correlates with symptomatic severity in patients with knee osteoarthritis. Annals of Clinical Biochemistry. 2015;**52**(2):276-282

[98] Beekhuizen M, Gierman LM, van Spil WE, Van Osch GJVM, Huizinga TWJ, Saris DBF, et al. An explorative study comparing levels of soluble mediators in control and osteoarthritic synovial fluid. Osteoarthritis and Cartilage. 2013;**21**(7):918-922

[99] Conde J, Scotece M, Gómez R, Lopez V, Gómez-Reino JJ, Gualillo O. Adipokines and osteoarthritis: Novel molecules involved in the pathogenesis and progression of disease. Arthritis.

[100] Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJVM, Van Offel JF, Verhaar JAN, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: A narrative review. Osteoarthritis and Cartilage.

[101] Geng Y, Blanco FJ, Cornelisson M, Lotz M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes. Journal of Immunology.

[102] Martel-Pelletier J, Pelletier JP, Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues.

2011;**2011**:1-8

2010;**18**(7):876-882

1995;**155**(2):796-801

**38**

## Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results

*Edoardo De Fenu, Berardino Di Paola, Marco Ruggiero, Bruno Carlesimo, Andrea Conversi and Ezio Adriani*

#### **Abstract**

Osteoarthritis (OA) represents one of the most common causes of joint pain and disability with related changes in bone morphology. In last years, this pathology is steadily increasing due to the continuous increase in the average life expectancy and the rate of active population. In recent years, there have been many conservative treatments for symptomatic gonarthrosis in order to reduce pain and delay or avoid the implantation of a knee prosthesis. The most studied and used was infiltrating treatment. Our group has been paying attention to regenerative medicine for many years, focusing on the characteristics of adipose tissue and the presence of multipotent mesenchymal cells, particularly in the vascular stromal area. Mesenchymal stem cells (MSCs) of adipose tissue can commit toward the chondrogenic, osteogenic, adipogenic, myogenic, and neurogenic lineages. Our group has continued the studies in this field by submitting this to treatment patients with grade II–III arthrosis according to the scale of Kellgren-Lawrence or patients with IV degree of such scale inoperable for internal reasons. To date, with a 4-year follow-up, our results are satisfactory in terms of pain reduction, improvement in joint function, and recovery of daily and sports activities.

**Keywords:** osteoarthritis, fat tissue, joint, adipose stem cells, conservative treatment

### **1. Introduction**

Osteoarthritis is a common degenerative joint cartilage disorder associated with hypertrophic bone changes and loss of joint cartilage integrity [1]. It causes pain, stiffness, and reduction of the associated function, consequently, disability with relative difficulty for the patient in carrying out the normal daily activities [2]. Risk factors are represented by genetic factors, female sex, post-traumatic conditions, age, obesity, etc. [3–6]. Treatment is therefore aimed at reducing symptoms, improving quality of life, and preventing its progression. Treatment options can be classified into:


Several national and international OA management guidelines recommend that patients should be first introduced into pathways that provide conservative treatment options and then directed to surgical treatment only when the conservative treatment does not allow the desired therapeutic achievement [7–10].

#### **2. Epidemiology and causes**

It represents the most common joint disease in the world, even if the frequencies vary from country to country: it affects more than 40 million individuals only in the United States and about 4 million in Italy, thus representing the main cause of disability at a national level. Therefore, OA is responsible for direct and indirect medical costs for society: clinical visits by primary care physicians or specialists, drugs, and surgical interventions represent direct costs; comorbidity and time lost from work due to the effects of disability are the examples of indirect costs. This clinical condition is more evident among the elderly, who may lose their independence and then need assistance during their daily activities, thus increasing the economic burden [11–13]. The lifetime risk of developing symptomatic osteoarthritis of the hip is 18.5% for men and 28.6% for women. For symptomatic knee OA, it is around 45%. Therefore, the risk of being subjected to a total hip or knee prosthesis at the age of 50 results to be high, with values of 7.1–11.6% for the hip and 8.1–10.8% for the knee [14, 15].

OA has a multifactorial etiology, and it is a disease that affects not only the quality of all synovial joint structures but also the function and quality of surrounding tissues and the pathway of nociceptive signaling. The causes that lead to the onset of osteoarthritis are largely unknown. On the other hand, it is believed that in most cases, many factors that alter the joint balance are involved. Schematically, the joint balance can be maintained if a normal load is exerted on a normal cartilage. Therefore, all factors capable of modifying this balance, acting either on the load or modifying the characteristics of cartilage, can be considered risk factors for osteoarthritis. In most cases, there is a combination between the genetic predisposition of the individual and the influence of environmental factors, especially those that act on the load, such as mechanical stress, obesity, malformations, trauma, and microtrauma. The precocity of the onset and the type of evolution may then depend on the number of factors involved, on their size and on the duration of their action. The OA can be divided into primary and secondary forms. The primary form, or idiopathic, manifests itself in intact joints without any triggering factor. Aging plays a fundamental role in this form of OA: the joint wear causes damage to the cartilage and, associated with an abnormal repair mechanism, the disease manifests itself. In the secondary form, OA is caused by a predisposing factor. In general, any violation of the integrity of the chondrocyte matrix has the potential to cause OA. However, some considerations aside highlight age as a risk factor. Although we all know that the frequency of arthrosis increases with age, arthritis is currently considered not to be a disease of aging. In fact, not all the elderly has this disease. It is therefore probable that the genetic tendency that an individual has in the predisposition to contract sooner or later some diseases, including arthritis, can be accentuated and accelerated by the risk factors. Obviously, among the elderly, the duration of exposure to these risk factors is higher, so the consequences are more evident.

Some risk factors are not changeable, such as age and genetic predisposition, while others, such as mechanical ones, overweight, etc., are considered modifiable and therefore, a rarely feasible consideration for other rheumatic diseases [16, 17].

**41**

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

cause of 10% of all total hip arthroplasty performed in the United States.

blood resulting in "death" bone. At this point, the healing response may be inadequate and then the joint surface collapses with the subsequent degenerative

preference. Among the risk factors acquired for osteonecrosis, alcohol abuse, smoking, and trauma are more common in men, while rheumatic diseases, such as systemic lupus erythematosus, are more commonly found in women. Therefore, the predilection of sex in osteonecrosis is highly influenced by the associated risk

OA develops with the combination of biochemical, cellular, and mechanical

OA is associated with biochemical events mediated by cytokines, proteolytic

Following the break of the cartilaginous matrix, due to proteolysis, the cartilage weakens and becomes subject to fibrillation and erosion, resulting in the release of proteoglycans and collagen fragments in the synovial fluid. This process induces an inflammatory response in the synovium, which causes further degradation of the cartilage. When the cartilage weakens, it begins to thin out, causing a reduction in joint space. Cartilage damage also causes the appearance of periarticular osteophytes. The exact mechanism of pain generation in OA is not well understood, but is

enzymes, and other proinflammatory substances responsible for osteolysis, subchondral bone sclerosis, osteophytosis, articular erosion of the cartilage, and

probably related to an interaction of different mechanisms [21, 24].

From a purely biochemical point of view, OA is the result of an imbalance between the peptides that promote the synthesis of components of the ECM (extracellular matrix) of the articular cartilage and those that induce the remodeling of

cartilage damage and induction of remodeling of the subchondral bone [32, 33]. The pathogenesis of OA is therefore composed of a network of overlapping complex molecular mechanisms, which entail damage to the articular tissue. These mechanisms depend on the equilibrium of expression of the catabolic and anabolic articular

The result of these catabolic cascades is the persistence of the synovitis, with initial

The goals of therapy in OA can be defined as "short-term," represented by pain control, stiffness control, and reduction of inflammation and "medium-long term," represented by the arrest or slowing of progression, by deformity prevention, and

For the pursuit of these objectives, many strategies can be used, both pharmacological and nonpharmacological, which often need to be coordinated with each other to be really effective. In fact, in addition to the introduction of new drug therapies, the importance of general measures, such as patient education to the

Attention must also be given to another attachment of the joints overlapping the OA for clinical and disability: osteonecrosis. Osteonecrosis is estimated to be the

However, differentiation between these conditions can be difficult, particularly

It is a disease characterized by the interruption of the normal supply of bone

Osteonecrosis is more common in patients under the age of 40 and has no sexual

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

arthritis [18].

factors [20].

processes [21].

these components. [25–31].

molecules.

**3. Therapy**

restoration of function.

at the beginning of the pathological process [18, 19].

thickening of the synovial membrane [22, 23].

#### *Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*

Attention must also be given to another attachment of the joints overlapping the OA for clinical and disability: osteonecrosis. Osteonecrosis is estimated to be the cause of 10% of all total hip arthroplasty performed in the United States.

However, differentiation between these conditions can be difficult, particularly at the beginning of the pathological process [18, 19].

It is a disease characterized by the interruption of the normal supply of bone blood resulting in "death" bone. At this point, the healing response may be inadequate and then the joint surface collapses with the subsequent degenerative arthritis [18].

Osteonecrosis is more common in patients under the age of 40 and has no sexual preference. Among the risk factors acquired for osteonecrosis, alcohol abuse, smoking, and trauma are more common in men, while rheumatic diseases, such as systemic lupus erythematosus, are more commonly found in women. Therefore, the predilection of sex in osteonecrosis is highly influenced by the associated risk factors [20].

OA develops with the combination of biochemical, cellular, and mechanical processes [21].

OA is associated with biochemical events mediated by cytokines, proteolytic enzymes, and other proinflammatory substances responsible for osteolysis, subchondral bone sclerosis, osteophytosis, articular erosion of the cartilage, and thickening of the synovial membrane [22, 23].

Following the break of the cartilaginous matrix, due to proteolysis, the cartilage weakens and becomes subject to fibrillation and erosion, resulting in the release of proteoglycans and collagen fragments in the synovial fluid. This process induces an inflammatory response in the synovium, which causes further degradation of the cartilage. When the cartilage weakens, it begins to thin out, causing a reduction in joint space. Cartilage damage also causes the appearance of periarticular osteophytes. The exact mechanism of pain generation in OA is not well understood, but is probably related to an interaction of different mechanisms [21, 24].

From a purely biochemical point of view, OA is the result of an imbalance between the peptides that promote the synthesis of components of the ECM (extracellular matrix) of the articular cartilage and those that induce the remodeling of these components. [25–31].

The result of these catabolic cascades is the persistence of the synovitis, with initial cartilage damage and induction of remodeling of the subchondral bone [32, 33]. The pathogenesis of OA is therefore composed of a network of overlapping complex molecular mechanisms, which entail damage to the articular tissue. These mechanisms depend on the equilibrium of expression of the catabolic and anabolic articular molecules.

#### **3. Therapy**

*Osteoarthritis Biomarkers and Treatments*

**2. Epidemiology and causes**

the knee [14, 15].

Several national and international OA management guidelines recommend that patients should be first introduced into pathways that provide conservative treatment options and then directed to surgical treatment only when the conservative

It represents the most common joint disease in the world, even if the frequencies vary from country to country: it affects more than 40 million individuals only in the United States and about 4 million in Italy, thus representing the main cause of disability at a national level. Therefore, OA is responsible for direct and indirect medical costs for society: clinical visits by primary care physicians or specialists, drugs, and surgical interventions represent direct costs; comorbidity and time lost from work due to the effects of disability are the examples of indirect costs. This clinical condition is more evident among the elderly, who may lose their independence and then need assistance during their daily activities, thus increasing the economic burden [11–13]. The lifetime risk of developing symptomatic osteoarthritis of the hip is 18.5% for men and 28.6% for women. For symptomatic knee OA, it is around 45%. Therefore, the risk of being subjected to a total hip or knee prosthesis at the age of 50 results to be high, with values of 7.1–11.6% for the hip and 8.1–10.8% for

OA has a multifactorial etiology, and it is a disease that affects not only the quality of all synovial joint structures but also the function and quality of surrounding tissues and the pathway of nociceptive signaling. The causes that lead to the onset of osteoarthritis are largely unknown. On the other hand, it is believed that in most cases, many factors that alter the joint balance are involved. Schematically, the joint balance can be maintained if a normal load is exerted on a normal cartilage. Therefore, all factors capable of modifying this balance, acting either on the load or modifying the characteristics of cartilage, can be considered risk factors for osteoarthritis. In most cases, there is a combination between the genetic predisposition of the individual and the influence of environmental factors, especially those that act on the load, such as mechanical stress, obesity, malformations, trauma, and microtrauma. The precocity of the onset and the type of evolution may then depend on the number of factors involved, on their size and on the duration of their action. The OA can be divided into primary and secondary forms. The primary form, or idiopathic, manifests itself in intact joints without any triggering factor. Aging plays a fundamental role in this form of OA: the joint wear causes damage to the cartilage and, associated with an abnormal repair mechanism, the disease manifests itself. In the secondary form, OA is caused by a predisposing factor. In general, any violation of the integrity of the chondrocyte matrix has the potential to cause OA. However, some considerations aside highlight age as a risk factor. Although we all know that the frequency of arthrosis increases with age, arthritis is currently considered not to be a disease of aging. In fact, not all the elderly has this disease. It is therefore probable that the genetic tendency that an individual has in the predisposition to contract sooner or later some diseases, including arthritis, can be accentuated and accelerated by the risk factors. Obviously, among the elderly, the duration of exposure to these risk factors is higher, so the consequences are more evident. Some risk factors are not changeable, such as age and genetic predisposition, while others, such as mechanical ones, overweight, etc., are considered modifiable and therefore, a rarely feasible consideration for other rheumatic diseases [16, 17].

treatment does not allow the desired therapeutic achievement [7–10].

**40**

The goals of therapy in OA can be defined as "short-term," represented by pain control, stiffness control, and reduction of inflammation and "medium-long term," represented by the arrest or slowing of progression, by deformity prevention, and restoration of function.

For the pursuit of these objectives, many strategies can be used, both pharmacological and nonpharmacological, which often need to be coordinated with each other to be really effective. In fact, in addition to the introduction of new drug therapies, the importance of general measures, such as patient education to the

knowledge of the disease and the consequent implementation of some measures such as weight loss and gymnastics or the use of unloading orthoses is recommended [10, 34, 35].

For conservative treatment, today we have several strategies available that, as mentioned, where possible, must be evaluated and taken into account in relation to the clinical condition of the patient.

An increasingly important role in the conservative treatment of OA is represented by the infiltrative therapy that in recent years has proposed a wider range of solutions: from intra-articular anti-inflammatory therapy as a palliative treatment to an infiltrative solution that can restore joint homeostasis or that can possibly activate a regenerative process into the joint.

Intra-articular corticosteroid injections may be indicated after failing NSAIDs and acetaminophen, but some researchers suggest only using them once every 3 months for a maximum of 2 years due to negative potential side effects [36].

The mechanism underlying the anti-inflammatory efficacy of corticosteroid is multifactorial, but generally involves blocking antigen opsonization, leukocytic cell adhesion, and cytokine diapedesis within the capillary endothelium. Corticosteroids also attenuate the effects of IL-1, decrease leukotriene and prostaglandin release, and inhibit metalloproteases and immunoglobulin synthesis [37].

The duration of action of intra-articular corticosteroid injections remains controversial, with various studies quoting anywhere between 1 and 24 weeks. There is consensus that steroids provide relief to patients for approximately 1 week after injection.

Adverse effects of corticosteroid injections do exist; however, Handler and Wright first described radiographic evidence of destruction of the knee joint and cartilage after several corticosteroid injections [38]. The incidence of joint infection following corticosteroid administration is rare, but may be as high as one in 3000 patients, with an associated mortality rate of approximately 11%. Additional known complications include pain, skin atrophy, tendinopathy, and systemic hyperglycemia [39].

The use of this procedure results in an inconclusive recommendation strength [10].

#### **4. Hyaluronic acid injections**

HA plays a fundamental role in maintaining elasticity and viscosity of the synovial fluid and integrity of the connective tissues such as joints [40, 41]. Several studies have shown that HA is a chondroprotector: it synthesizes proteoglycan and glycosaminoglycan, and it has anti-inflammatory, mechanical, subchondral, and analgesic actions [40].

#### **5. Platelet-rich plasma**

Platelet-rich plasma (PRP) is the most investigated biological treatments [42–44] due to the capacity to reduce inflammation and consequently a reduction of pain [45–47]. PRP exerts its biological effect with neoangiogenesis and migration of macrophages and mesenchymal cells and regulates cell differentiation and the activity of different cell lines, promoting tissue regeneration. PRP is controversial for the treatment of OA, because there is insufficient evidence to recommend the use of it [48–50].

Despite the growing interest in this biological approach for cartilage regeneration, the knowledge on this topic is still preliminary [51].

**43**

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

The promise of mesenchymal stem cells (MSCs) to give birth to a new era of medicine was strong, thanks to the ability of these cells to do self-renewal and multipotent *in vitro* differentiation into mesodermal cell subtypes. To be honest, recent studies have demonstrated that a good portion of the thrilling *in vivo* clinical results is due to the trophic, paracrine, and immunomodulatory activities of MSCs instead of their differentiation ability [52]. Differently from drug concept where the effect is dependent from concentration, MSCs are self- and site-regulated and they release a multitude of bioactive factors in variable concentration in response to the local messages of the microenviroment. The main trophic activity exerted by MSCs is the release of growth factors and other chemokines to induce the homing and proliferation of cellular progenitors and to promote angiogenesis. These factors are transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF), endothelial growth factor (EGF), fibroblast growth factor 2 (FGF-2), and insulin-like growth factor 1 (IGF-1)—all of these are proteins able to accelerate cellular growth and division of progenitors [53]. Moreover, IGF-1, EGF, and the vascular endothelial growth factor (VEGF) are able to recruit endothelial cells and promote new vascularization [54]. MSCs can derive from many tissue sources, and among these, the more manageable for clinical practice is bone marrow and adipose tissue. Even if the MSCs from bone marrow (BM-MSCs) were discovered first and have more clinical experience, there is higher interest on adipose tissue—not only for the ease and low morbidity of harvest but also because it has a higher MSCs frequency. In a bone marrow aspirate,

/ml nucleated cells and, among these, only 0.001–0.01% are MSCs;

/g of MSCs, it means that there is a 500-fold higher

MSCs frequency ranges from 1 to 10% based on the donor site. Since the adipose tis-

concentration of MSCs in comparison with bone marrow [55]. Moreover, it has been demonstrated that the proliferation and differentiation properties of stem cells from adipose tissue (ADSCs) are less impaired by age in comparison with BM-MSCs [56]. ADSCs can be exploited with three different methods. The first, the only option where we can properly name them as true ADSCs, is the cell culture and optional cell expansion *in vitro*. By selecting the cells that are able to stick to the plastic, it is possible to obtain cell that expresses mesenchymal markers (CD105+, CD73+, CD90+, CD45−, CD34−, CD11b−, CD14−, CD79a−, and HLA-DR−) able to differentiate into the three mesodermal lineages (bone, cartilage, and fat). This option has serious limitation in the clinical practice due to regulatory issues because it can only be performed into good manufacturing practice facilities that manipulate these cells like an experimental drug (it is named advanced cellular therapy). Notably, concentrated BM-MSCs outperform cultured cells since they are more practical and efficient and less harmful and expensive [52]. The second method is enzymatic digestion of adipose tissue that gives in the hands of operators a heterogeneous cell population that contains, beside MSCs, endothelial cells, leucocytes, and preadipocytes. This final product of enzymatic digestion is named stromal vascular-fraction (SVF). Finally, autologous ADSCs can be exploited through the processing and fragmentation of adipose tissue (FAT, *fragmented adipose tissue*). While the SVF is a heterogeneous cell population where each cell is separated from the others and the efficacy is dose-dependent, the FAT is a proper minimally manipulated tissue that entrust more on cell quality instead of cell quantity. The FAT is composed of tissue cluster of variable diameter where the SVF cells are embedded and attached to an undisrupted tissue architecture made of vasculature and extracellular matrix sustained by a scaffold made of adipocytes. This natural scaffold protects cells from anoikis (death cause by the lack of cellular adherence) and other harmful stress.

/g nucleated cells where the

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

**6. Biological use of fat tissue**

there are 6 × 106

sue has a total of 0.5 × 104

on the other hand, a lipoaspirate contains 0.5–2.0 × 106

–2 × 105

#### **6. Biological use of fat tissue**

*Osteoarthritis Biomarkers and Treatments*

the clinical condition of the patient.

activate a regenerative process into the joint.

mended [10, 34, 35].

after injection.

hyperglycemia [39].

analgesic actions [40].

use of it [48–50].

**5. Platelet-rich plasma**

**4. Hyaluronic acid injections**

knowledge of the disease and the consequent implementation of some measures such as weight loss and gymnastics or the use of unloading orthoses is recom-

For conservative treatment, today we have several strategies available that, as mentioned, where possible, must be evaluated and taken into account in relation to

An increasingly important role in the conservative treatment of OA is represented by the infiltrative therapy that in recent years has proposed a wider range of solutions: from intra-articular anti-inflammatory therapy as a palliative treatment to an infiltrative solution that can restore joint homeostasis or that can possibly

Intra-articular corticosteroid injections may be indicated after failing NSAIDs and acetaminophen, but some researchers suggest only using them once every 3 months for a maximum of 2 years due to negative potential side effects [36].

The mechanism underlying the anti-inflammatory efficacy of corticosteroid is multifactorial, but generally involves blocking antigen opsonization, leukocytic cell adhesion, and cytokine diapedesis within the capillary endothelium. Corticosteroids also attenuate the effects of IL-1, decrease leukotriene and prostaglandin release, and inhibit metalloproteases and immunoglobulin synthesis [37]. The duration of action of intra-articular corticosteroid injections remains controversial, with various studies quoting anywhere between 1 and 24 weeks. There is consensus that steroids provide relief to patients for approximately 1 week

Adverse effects of corticosteroid injections do exist; however, Handler and Wright first described radiographic evidence of destruction of the knee joint and cartilage after several corticosteroid injections [38]. The incidence of joint infection following corticosteroid administration is rare, but may be as high as one in 3000 patients, with an associated mortality rate of approximately 11%. Additional known complications include pain, skin atrophy, tendinopathy, and systemic

The use of this procedure results in an inconclusive recommendation strength [10].

HA plays a fundamental role in maintaining elasticity and viscosity of the synovial fluid and integrity of the connective tissues such as joints [40, 41]. Several studies have shown that HA is a chondroprotector: it synthesizes proteoglycan and glycosaminoglycan, and it has anti-inflammatory, mechanical, subchondral, and

Platelet-rich plasma (PRP) is the most investigated biological treatments [42–44] due to the capacity to reduce inflammation and consequently a reduction of pain [45–47]. PRP exerts its biological effect with neoangiogenesis and migration of macrophages and mesenchymal cells and regulates cell differentiation and the activity of different cell lines, promoting tissue regeneration. PRP is controversial for the treatment of OA, because there is insufficient evidence to recommend the

Despite the growing interest in this biological approach for cartilage regenera-

tion, the knowledge on this topic is still preliminary [51].

**42**

The promise of mesenchymal stem cells (MSCs) to give birth to a new era of medicine was strong, thanks to the ability of these cells to do self-renewal and multipotent *in vitro* differentiation into mesodermal cell subtypes. To be honest, recent studies have demonstrated that a good portion of the thrilling *in vivo* clinical results is due to the trophic, paracrine, and immunomodulatory activities of MSCs instead of their differentiation ability [52]. Differently from drug concept where the effect is dependent from concentration, MSCs are self- and site-regulated and they release a multitude of bioactive factors in variable concentration in response to the local messages of the microenviroment. The main trophic activity exerted by MSCs is the release of growth factors and other chemokines to induce the homing and proliferation of cellular progenitors and to promote angiogenesis. These factors are transforming growth factor beta (TGF-β), hepatocyte growth factor (HGF), endothelial growth factor (EGF), fibroblast growth factor 2 (FGF-2), and insulin-like growth factor 1 (IGF-1)—all of these are proteins able to accelerate cellular growth and division of progenitors [53]. Moreover, IGF-1, EGF, and the vascular endothelial growth factor (VEGF) are able to recruit endothelial cells and promote new vascularization [54].

MSCs can derive from many tissue sources, and among these, the more manageable for clinical practice is bone marrow and adipose tissue. Even if the MSCs from bone marrow (BM-MSCs) were discovered first and have more clinical experience, there is higher interest on adipose tissue—not only for the ease and low morbidity of harvest but also because it has a higher MSCs frequency. In a bone marrow aspirate, there are 6 × 106 /ml nucleated cells and, among these, only 0.001–0.01% are MSCs; on the other hand, a lipoaspirate contains 0.5–2.0 × 106 /g nucleated cells where the MSCs frequency ranges from 1 to 10% based on the donor site. Since the adipose tissue has a total of 0.5 × 104 –2 × 105 /g of MSCs, it means that there is a 500-fold higher concentration of MSCs in comparison with bone marrow [55]. Moreover, it has been demonstrated that the proliferation and differentiation properties of stem cells from adipose tissue (ADSCs) are less impaired by age in comparison with BM-MSCs [56].

ADSCs can be exploited with three different methods. The first, the only option where we can properly name them as true ADSCs, is the cell culture and optional cell expansion *in vitro*. By selecting the cells that are able to stick to the plastic, it is possible to obtain cell that expresses mesenchymal markers (CD105+, CD73+, CD90+, CD45−, CD34−, CD11b−, CD14−, CD79a−, and HLA-DR−) able to differentiate into the three mesodermal lineages (bone, cartilage, and fat). This option has serious limitation in the clinical practice due to regulatory issues because it can only be performed into good manufacturing practice facilities that manipulate these cells like an experimental drug (it is named advanced cellular therapy). Notably, concentrated BM-MSCs outperform cultured cells since they are more practical and efficient and less harmful and expensive [52]. The second method is enzymatic digestion of adipose tissue that gives in the hands of operators a heterogeneous cell population that contains, beside MSCs, endothelial cells, leucocytes, and preadipocytes. This final product of enzymatic digestion is named stromal vascular-fraction (SVF). Finally, autologous ADSCs can be exploited through the processing and fragmentation of adipose tissue (FAT, *fragmented adipose tissue*). While the SVF is a heterogeneous cell population where each cell is separated from the others and the efficacy is dose-dependent, the FAT is a proper minimally manipulated tissue that entrust more on cell quality instead of cell quantity. The FAT is composed of tissue cluster of variable diameter where the SVF cells are embedded and attached to an undisrupted tissue architecture made of vasculature and extracellular matrix sustained by a scaffold made of adipocytes. This natural scaffold protects cells from anoikis (death cause by the lack of cellular adherence) and other harmful stress.

The MSCs embedded into these clusters have high vitality and can still differentiate into the three mesodermal lineages as a proof of their multipotency. To prove that quality is superior to quantity, it has been demonstrated in an animal model of critical limb ischemia that an injection of 500 μl of FAT (which contain 2 × 104 ADSC) restores limb perfusion better than a single injection of 1 × 106 isolated ADSC [57].

During the First World War, the fat was used to heal soldier wounds and its application was very heterogeneous until 1990 where Sidney Coleman defined precise guidelines. The evolution of surgical techniques associated the volumizing effect of lipofilling to the regenerative properties of natural adipose tissue, favoring the processing, the reduction, and the purification of the tissue to raise the survival of grafts and magnify the regenerative potential of MSCs. Also reducing the volume of grafts and the diameter of injection needles had helped the hosting tissue to decrease stress and trauma, thus provoking less inflammation and ameliorating again graft survival [58]. Adipose tissue is now used with lipofilling techniques in hard-toheal wounds and in all cases characterized by mortified tissue (burn, compression, and radiation) linking the regenerative potential also to an esthetic effect. Wound healing professionals use lipofilling to treat ulcers resistant to classical therapies and advanced dressing and also for the treatment of critical limb ischemia and diabetic patients [59]. In orthopedics, intra-articular lipofilling has become a fashionable and innovative strategy to fight osteoarthritis, thanks to the ability of this tissue product to reequilibrate the articular homeostasis and to reduce the inflammation of the synovial membrane [60]. The integrity of the extracellular matrix can also exploit the shock absorber function of adipose tissue reducing the stress between cartilage surfaces. The paracrine effect of MSCs can also promote cartilage repair when mechanical conditions of the articulation are stable. The anti-adhesive properties of adipose tissue were exploited in the surgery of tendons and nerves to limit the formation of fibrotic and scarring tissue, thus also limiting the relapse incidence. Finally, adipose tissue was also studied in pain management for the intradiscal infiltration for the treatment of low back pain associated to black disc.

#### **7. Lipofilling**

The technique of liposculture is originally created for esthetic purposes. Autologous fat transfer has recently become an increasingly popular surgical procedure: harvesting, refinement/processing, and transfer of subcutaneous tissue to provide relatively pure and intact parcels of fat are paramount for successful lipofilling. Usually, we use local anesthesia with sedation or epidural anesthesia. Rarely, we use general anesthesia.

• Incisions with a n°11 blade are made in the donor site. When possible, incisions are placed in wrinkle lines, folds, or fatty areas (abdomen flank, thigh, and knee).

Instruments for lipofilling cause minimal trauma to fatty tissue during placement.

• Cannulas vary in shape (curved or no-curved) and length (7–12 cm).

Liposuction: special blunt-tip, maximum diameter 3 mm, with small holes near the tip

○ Coleman I is used near a blood vessels or nerve. This cannula is capped on the tip with a lip that extends 180° over the distal aperture.

**45**

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

flat on the end to allow for dissection of the tissue.

○ Coleman V is a dissector used for scar's treatment.

**8.1 Harvesting of adipose tissue from a suitable donor site**

○ Coleman II is used in other circumstances. This cannula is not completely capped and has a lip that extends over the distal aperture about 130–150°.

○ Coleman III is used for the scars or fibrous tissue treatments. This cannula is

○ Infiltration cannula is a blunt 17G cannula with one or two distal aperture proximal to the tip: no fatty tissue should be infiltrated during the advancement of the cannula; fatty tissue is left in the pathway of the retreating blunt cannula (this method permits stable and regulated placement with minimal

Many different techniques have been proposed for harvesting of adipose tissue: the fundamental aim is minimizing adipocyte damage and increasing the survival of adipose tissue. Incisions with a n°11 blade are made in the donor site, when possible in wrinkle lines, folds, or fatty areas (abdomen, flank, thigh, and knee).

There are many different natural fat deposits: it is important an accurate preop-

The abdomen is the most common site of fat harvesting; it is also common in the trochanteric region (saddlebags) and in the medial/internal part of the thighs and knees. The main techniques for fat harvesting are vacuum suction, syringe suction, or

Other surgeons advocate a "dry" fat harvesting: cell viability has been similar to "wet" fat harvesting nut, and this technique may lead to a greater requirement for analgesic.

In 1993, Klein proposed a new method called tumescent technique in which a fluid solution (Klein's solution) was injected into the donor site improving the safety of large-volume liposuction (it eliminated the need for general anesthesia

the use of a water-jet system to harvest the fat tissue and collect it in a closed container: minimal bruising and postoperative pain, faster harvesting time, and

into fatty tissue engorged with tumescent fluid (Klein's solution)

Another technique is the "Berlin autologous lipotransplantation", which involves

In the course of fat harvesting, a blunt cannula is inserted through an incision

• Negative pressure liposuction is faster than 10 ml syringe aspiration (low pressure) and is an effective method for aspiration of large amounts of fat, but it causes massive destruction of adipocytes, greatly reducing the survival of fat graft.

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

Transplantation: small blunt-tip

**8. Surgical technique**

surgical excision.

*8.1.1 DRY technique*

*8.1.2 WET technique*

greater sterility.

erative examination of the patient.

and reduced surgical hemorrhage).

irregularities or clumps of tissue).

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*


Transplantation: small blunt-tip

○ Infiltration cannula is a blunt 17G cannula with one or two distal aperture proximal to the tip: no fatty tissue should be infiltrated during the advancement of the cannula; fatty tissue is left in the pathway of the retreating blunt cannula (this method permits stable and regulated placement with minimal irregularities or clumps of tissue).

#### **8. Surgical technique**

*Osteoarthritis Biomarkers and Treatments*

The MSCs embedded into these clusters have high vitality and can still differentiate into the three mesodermal lineages as a proof of their multipotency. To prove that quality is superior to quantity, it has been demonstrated in an animal model of criti-

During the First World War, the fat was used to heal soldier wounds and its application was very heterogeneous until 1990 where Sidney Coleman defined precise guidelines. The evolution of surgical techniques associated the volumizing effect of lipofilling to the regenerative properties of natural adipose tissue, favoring the processing, the reduction, and the purification of the tissue to raise the survival of grafts and magnify the regenerative potential of MSCs. Also reducing the volume of grafts and the diameter of injection needles had helped the hosting tissue to decrease stress and trauma, thus provoking less inflammation and ameliorating again graft survival [58]. Adipose tissue is now used with lipofilling techniques in hard-toheal wounds and in all cases characterized by mortified tissue (burn, compression, and radiation) linking the regenerative potential also to an esthetic effect. Wound healing professionals use lipofilling to treat ulcers resistant to classical therapies and advanced dressing and also for the treatment of critical limb ischemia and diabetic patients [59]. In orthopedics, intra-articular lipofilling has become a fashionable and innovative strategy to fight osteoarthritis, thanks to the ability of this tissue product to reequilibrate the articular homeostasis and to reduce the inflammation of the synovial membrane [60]. The integrity of the extracellular matrix can also exploit the shock absorber function of adipose tissue reducing the stress between cartilage surfaces. The paracrine effect of MSCs can also promote cartilage repair when mechanical conditions of the articulation are stable. The anti-adhesive properties of adipose tissue were exploited in the surgery of tendons and nerves to limit the formation of fibrotic and scarring tissue, thus also limiting the relapse incidence. Finally, adipose tissue was also studied in pain management for the intradiscal infiltration for

ADSC)

isolated ADSC [57].

cal limb ischemia that an injection of 500 μl of FAT (which contain 2 × 104

restores limb perfusion better than a single injection of 1 × 106

the treatment of low back pain associated to black disc.

The technique of liposculture is originally created for esthetic purposes. Autologous fat transfer has recently become an increasingly popular surgical procedure: harvesting, refinement/processing, and transfer of subcutaneous tissue to provide relatively pure and intact parcels of fat are paramount for successful lipofilling. Usually, we use local anesthesia with sedation or epidural anesthesia.

• Incisions with a n°11 blade are made in the donor site. When possible, incisions are placed in wrinkle lines, folds, or fatty areas (abdomen flank, thigh, and

Instruments for lipofilling cause minimal trauma to fatty tissue during placement.

Liposuction: special blunt-tip, maximum diameter 3 mm, with small holes near

○ Coleman I is used near a blood vessels or nerve. This cannula is capped on the

• Cannulas vary in shape (curved or no-curved) and length (7–12 cm).

tip with a lip that extends 180° over the distal aperture.

**44**

the tip

**7. Lipofilling**

knee).

Rarely, we use general anesthesia.

#### **8.1 Harvesting of adipose tissue from a suitable donor site**

Many different techniques have been proposed for harvesting of adipose tissue: the fundamental aim is minimizing adipocyte damage and increasing the survival of adipose tissue. Incisions with a n°11 blade are made in the donor site, when possible in wrinkle lines, folds, or fatty areas (abdomen, flank, thigh, and knee).

There are many different natural fat deposits: it is important an accurate preoperative examination of the patient.

The abdomen is the most common site of fat harvesting; it is also common in the trochanteric region (saddlebags) and in the medial/internal part of the thighs and knees.

The main techniques for fat harvesting are vacuum suction, syringe suction, or surgical excision.

#### *8.1.1 DRY technique*

Other surgeons advocate a "dry" fat harvesting: cell viability has been similar to "wet" fat harvesting nut, and this technique may lead to a greater requirement for analgesic.

#### *8.1.2 WET technique*

In 1993, Klein proposed a new method called tumescent technique in which a fluid solution (Klein's solution) was injected into the donor site improving the safety of large-volume liposuction (it eliminated the need for general anesthesia and reduced surgical hemorrhage).

Another technique is the "Berlin autologous lipotransplantation", which involves the use of a water-jet system to harvest the fat tissue and collect it in a closed container: minimal bruising and postoperative pain, faster harvesting time, and greater sterility.

In the course of fat harvesting, a blunt cannula is inserted through an incision into fatty tissue engorged with tumescent fluid (Klein's solution)

• Negative pressure liposuction is faster than 10 ml syringe aspiration (low pressure) and is an effective method for aspiration of large amounts of fat, but it causes massive destruction of adipocytes, greatly reducing the survival of fat graft.

• Conventional liposuction with high negative pressure may cause disruption of 90% of adipocytes structures.

Cannula size may also impact the viability of harvested adipocytes. Performing biopsy and lipoaspiration with large-bore cannulas could reduce the risk of cellular rupture by preserving native tissue structure.

So the size of cannula must be large enough to preserve adipocytes and stromal cells and their anatomical relationship without limiting diffusion of nutrients.

Coleman described a technique for fat harvest that minimized trauma to the adipocytes.

He used 3-mm incisions (n°11 blade), a 3-mm blunt edge, 2 hole harvesting cannulas (3 mm) connected to a 10-ml Luer-Lock syringe. The cannula is pushed through the harvest site (abdomen, flank, thigh, knee, or other sites with excess adipose tissue) as the surgeon uses digital manipulation to create a gentle negative pressure.

A combination of lower negative pressure and the curetting action of the cannula through the tissues allows parcels of fat to move into the syringe. At the end, the syringe is disconnected from the cannula and replaced with a plug that seals the Luer-Lock end of the syringe.

#### **8.2 Processing**

The most commonly used methods to process fat tissue are centrifugation, sedimentation, washing, and filtration. Comparative studies investigating the effects of fat processing with different techniques have showed no significant differences in fat retention.

The goal of fat processing is:

To eliminate contaminants that can cause inflammation at the recipient site, which can be detrimental for the fat graft. These elements include cellular debris, free oil, and other nonviable components of the lipoaspirate such as hematogenous cells.


#### **8.3 Ensuring graft viability**

Centrifugation is the most widely used technique for postharvest fat processing and has previously been considered the criterion standard. Coleman's technique consisted in centrifugation (3000 rpm for 3 minutes) to separate the different components as follows:

**47**

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

The supernatant fat and the lower aqueous layers are discarded, leaving concen-

That is an optimal method to obtain the highest concentration of stem cells and increased angiogenic grow factors (FGF and VEGF). It separates adipocytes from blood cells and enzymes (lipids, proteases, and lipases). Sedimentation allows

Washing methods has the goal of removing superfluous tumescent fluid and all

• Lipocell technique is a new procedure that allows eliminating blood, oil, cellular debris, or other nonviable components and obtaining a pure lipoaspirate. This technique preserves a large number of mesenchymal stem cells and a large

Filtration allows elimination of contaminants by maintaining viable adipocytes and

Principles of fat reimplantation are found on optimal recipient site vascularity to

Neovascularization progresses 1 mm/day; therefore, a deposit diameter greater than 2 mm should be avoided to prevent central necrosis. With a skin incision like a diameter of the cannula, the graft is put at the level of the anatomical region involved. Cannulas with small gauge will reduce tissue trauma, bleeding, and hematoma.

Through multiple access sites, multiple tunnels are created on insertion, but fat

In our experience, mainly concentrated on the knee involves the constant association of a diagnostic and surgical arthroscopy; in fact, in the majority of cases, there are meniscal lesions (flap type) or unstable chondral lesions which, if left

All steps in surgical technique (harvesting, processing, and transplantation) are important. Complications are few, rare, and minimal. Viability of fat cells is crucial. The chances of survival are higher if the fat graft is less manipulated and reinjected

• Donor site complications related to lipoaspirate technique: bruising, swelling, hematoma, pain, paresthesia, infection, pathologic scarring, contour irregu-

• Failure of fat graft in recipient sites could cause fat necrosis, oil cysts, calcifications, reabsorption of fat, and intravascular injection with fat embolism.

a lot of ADSC, thus obtaining a viable graft material for large volume fat transfers.

mechanism is known to work by principles similar to a dialysis unit.

Graft can survive up to 48 hours by tissue fluid absorption.

untreated, could lead to failure of the grafting procedure alone.

larities, cellulitis, and damage to the underlying structures.

is injected only during withdrawal of the cannula.

Early identification of local sepsis.

• Pure graft filtration is a new technology that uses a closed-membrane filtration system for preparation and isolation of stromal vascular fraction and its

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

obtaining a large number of vital intact adipocytes [61].

elements that can be detrimental for the fat graft.

number of adipocytes.

**8.4 Implantation/fat injection**

increas fat survival.

**9. Complications**

as fast as possible.

trated viable fat cells.


*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*

The supernatant fat and the lower aqueous layers are discarded, leaving concentrated viable fat cells.

That is an optimal method to obtain the highest concentration of stem cells and increased angiogenic grow factors (FGF and VEGF). It separates adipocytes from blood cells and enzymes (lipids, proteases, and lipases). Sedimentation allows obtaining a large number of vital intact adipocytes [61].

Washing methods has the goal of removing superfluous tumescent fluid and all elements that can be detrimental for the fat graft.

• Lipocell technique is a new procedure that allows eliminating blood, oil, cellular debris, or other nonviable components and obtaining a pure lipoaspirate. This technique preserves a large number of mesenchymal stem cells and a large number of adipocytes.

Filtration allows elimination of contaminants by maintaining viable adipocytes and a lot of ADSC, thus obtaining a viable graft material for large volume fat transfers.

• Pure graft filtration is a new technology that uses a closed-membrane filtration system for preparation and isolation of stromal vascular fraction and its mechanism is known to work by principles similar to a dialysis unit.

#### **8.4 Implantation/fat injection**

*Osteoarthritis Biomarkers and Treatments*

adipocytes.

pressure.

**8.2 Processing**

fat retention.

fat.

cells.

Luer-Lock end of the syringe.

The goal of fat processing is:

confused with volume correction.

**8.3 Ensuring graft viability**

components as follows:

• Middle: primarily fatty tissue.

ing the number of ADSC in the graft material.

• Upper level: least dense and consists primarily of oil.

• Lowest: blood, water, and aqueous elements.

90% of adipocytes structures.

rupture by preserving native tissue structure.

• Conventional liposuction with high negative pressure may cause disruption of

Cannula size may also impact the viability of harvested adipocytes. Performing biopsy and lipoaspiration with large-bore cannulas could reduce the risk of cellular

So the size of cannula must be large enough to preserve adipocytes and stromal

cells and their anatomical relationship without limiting diffusion of nutrients. Coleman described a technique for fat harvest that minimized trauma to the

He used 3-mm incisions (n°11 blade), a 3-mm blunt edge, 2 hole harvesting cannulas (3 mm) connected to a 10-ml Luer-Lock syringe. The cannula is pushed through the harvest site (abdomen, flank, thigh, knee, or other sites with excess adipose tissue) as the surgeon uses digital manipulation to create a gentle negative

A combination of lower negative pressure and the curetting action of the cannula through the tissues allows parcels of fat to move into the syringe. At the end, the syringe is disconnected from the cannula and replaced with a plug that seals the

The most commonly used methods to process fat tissue are centrifugation, sedimentation, washing, and filtration. Comparative studies investigating the effects of fat processing with different techniques have showed no significant differences in

To eliminate contaminants that can cause inflammation at the recipient site, which can be detrimental for the fat graft. These elements include cellular debris, free oil, and other nonviable components of the lipoaspirate such as hematogenous

• Blood must be extracted in order to improve degradation of the transplanted

• Moreover, many authors report an improvement in graft viability by maximiz-

Centrifugation is the most widely used technique for postharvest fat processing and has previously been considered the criterion standard. Coleman's technique consisted in centrifugation (3000 rpm for 3 minutes) to separate the different

• Since the debris will be absorbed after a few hours, its injection could be

**46**

Principles of fat reimplantation are found on optimal recipient site vascularity to increas fat survival.

Graft can survive up to 48 hours by tissue fluid absorption.

Neovascularization progresses 1 mm/day; therefore, a deposit diameter greater than 2 mm should be avoided to prevent central necrosis. With a skin incision like a diameter of the cannula, the graft is put at the level of the anatomical region involved. Cannulas with small gauge will reduce tissue trauma, bleeding, and hematoma.

Through multiple access sites, multiple tunnels are created on insertion, but fat is injected only during withdrawal of the cannula.

In our experience, mainly concentrated on the knee involves the constant association of a diagnostic and surgical arthroscopy; in fact, in the majority of cases, there are meniscal lesions (flap type) or unstable chondral lesions which, if left untreated, could lead to failure of the grafting procedure alone.

#### **9. Complications**

All steps in surgical technique (harvesting, processing, and transplantation) are important. Complications are few, rare, and minimal. Viability of fat cells is crucial. The chances of survival are higher if the fat graft is less manipulated and reinjected as fast as possible.


Early identification of local sepsis.

### **10. Conclusion**

In conclusion, there are several treatments for knee OA including nonpharmacological and pharmacological treatments.

Among the nonpharmacological ones, patient education and self-management strategies, advising weight loss and strengthening programs are included.

Regarding the pharmacological treatment, the NSAIDs can be used in the shortterm therapy but their effect is limited in time.

Another employed strategy to manage knee OA is represented by joint injections of corticosteroids, hyaluronic acid, PRP, and even stem cells [47].

The reason for using ASCs in orthopedics is derived from tissue engineering studies that enhance their ability to differentiate into osteoblastic or chondrocyte using appropriate culture media and bioengineered structures that can accommodate cells as a biological scaffold.

The studies of Hattori and colleagues showed an osteogenic differentiation (by electron microscope, with histological evaluation and by the capacity of osteocalcin secretion) analogous to BMSC using a beta-tricalciophosphate scaffold [62, 63].

Always Hattori and colleagues in 2008 proposed new strategies for the in vitro expansion of ASCs. In most cases, the expansion was obtained with fetal bovine serum (FBS) which, in subsequent clinical applications, could have caused infections or immunological reactions caused by the proteins present in the FBS [64].

For this reason, Hattori and colleagues have demonstrated, with studies on the mouse, that it is possible to obtain the expansion of the ASC with the same differentiation potentials, using a small amount of autologous serum containing type I, FGF-2 collagen and thus opening the way to possible therapeutic applications.

Promising is the application in the treatment of cartilaginous lesions. In 2007, Masuoka and colleagues used a three-dimensional honeycomb scaffold of atelocollagene (ACHMS scaffold) with ASCs for cartilaginous lesions in rabbit's knees; as a control group, they used the only ACHMS-scaffold or nothing [65]. Twelve weeks later, histological analyzes have highlighted that only in cases where ASC + ACHMS-scaffold had been used, there was hyaline cartilage with high expression of type II collagen. It should be also noted that the ASCs, as mentioned above, have the ability to release factors of tissue growth and/or regeneration and cytokines. These substances play an important role in chemotaxis, in promoting tissue regeneration, cell differentiation, and neoangiogenesis.

Regenerative medicine opens the way for a new therapeutic frontier, as it now allows an improvement in symptoms and in the functionality of the joints. On the other hand, further studies are needed, major follow-ups, targeted clinical trials, and finally the possibility of a second look to evaluate and validate the real regenerative capacity of this treatment.

**49**

**Author details**

Edoardo De Fenu1

Andrea Conversi1

provided the original work is properly cited.

2 Mater Dei Sport Clinique, Rome, Italy

3 Mater Dei Clinique, Rome, Italy

\*, Berardino Di Paola<sup>2</sup>

and Ezio Adriani2

1 Policlinico Umberto I Università Sapienza, Rome, Italy

\*Address all correspondence to: edoardodefenu@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Marco Ruggiero3

, Bruno Carlesimo3

,

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*

### **Author details**

*Osteoarthritis Biomarkers and Treatments*

logical and pharmacological treatments.

date cells as a biological scaffold.

term therapy but their effect is limited in time.

In conclusion, there are several treatments for knee OA including nonpharmaco-

Among the nonpharmacological ones, patient education and self-management

Regarding the pharmacological treatment, the NSAIDs can be used in the short-

Another employed strategy to manage knee OA is represented by joint injections

The reason for using ASCs in orthopedics is derived from tissue engineering studies that enhance their ability to differentiate into osteoblastic or chondrocyte using appropriate culture media and bioengineered structures that can accommo-

The studies of Hattori and colleagues showed an osteogenic differentiation (by electron microscope, with histological evaluation and by the capacity of osteocalcin secretion) analogous to BMSC using a beta-tricalciophosphate scaf-

Always Hattori and colleagues in 2008 proposed new strategies for the in vitro expansion of ASCs. In most cases, the expansion was obtained with fetal bovine serum (FBS) which, in subsequent clinical applications, could have caused infections or immunological reactions caused by the proteins present in

For this reason, Hattori and colleagues have demonstrated, with studies on the mouse, that it is possible to obtain the expansion of the ASC with the same differentiation potentials, using a small amount of autologous serum containing type I, FGF-2 collagen and thus opening the way to possible therapeutic

Promising is the application in the treatment of cartilaginous lesions. In 2007, Masuoka and colleagues used a three-dimensional honeycomb scaffold of atelocollagene (ACHMS scaffold) with ASCs for cartilaginous lesions in rabbit's knees; as a control group, they used the only ACHMS-scaffold or nothing [65]. Twelve weeks later, histological analyzes have highlighted that only in cases where ASC + ACHMS-scaffold had been used, there was hyaline cartilage with high expression of type II collagen. It should be also noted that the ASCs, as mentioned above, have the ability to release factors of tissue growth and/or regeneration and cytokines. These substances play an important role in chemotaxis, in promoting tissue regeneration, cell differentiation, and

Regenerative medicine opens the way for a new therapeutic frontier, as it now allows an improvement in symptoms and in the functionality of the joints. On the other hand, further studies are needed, major follow-ups, targeted clinical trials, and finally the possibility of a second look to evaluate and validate the real regen-

strategies, advising weight loss and strengthening programs are included.

of corticosteroids, hyaluronic acid, PRP, and even stem cells [47].

**10. Conclusion**

fold [62, 63].

the FBS [64].

applications.

neoangiogenesis.

erative capacity of this treatment.

**48**

Edoardo De Fenu1 \*, Berardino Di Paola<sup>2</sup> , Marco Ruggiero3 , Bruno Carlesimo3 , Andrea Conversi1 and Ezio Adriani2

1 Policlinico Umberto I Università Sapienza, Rome, Italy


\*Address all correspondence to: edoardodefenu@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Goodman S. Osteoarthritis. In: Yee A, Paget S, editors. Expert Guide to Rheumatology. Philadelphia, PA: American College of Physicians; 2005. pp. 269-283

[2] Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: An update with relevance for clinical practice. Lancet. 2011;**377**:2115-2126

[3] DiCesare PE, Abramson S, Samuels J. Pathogenesis of osteoarthritis. In: Firestein GS, Kelley WN, editors. Kelley's Textbook of Rheumatology. 8th ed. Philadelphia, PA, Saunders Elsevier; 2009

[4] Bateman JF. Genetic aspects of osteoarthritis. Seminars in Arthritis and Rheumatism. 2005;**34**(6 Suppl 2):15-18

[5] Ryder JJ, Garrison K, Song F, et al. Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: A systematic review. Annals of the Rheumatic Diseases. 2008;**67**(5):584-591

[6] Valdes AM, Spector TD. The genetic epidemiology of osteoarthritis. Current Opinion in Rheumatology. 2010;**22**(2):139-143

[7] McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis and Cartilage. 2014;**22**:363-388

[8] Smink AJ, van den Ende CH, Vliet Vlieland TP, Swierstra BA, Kortland JH, Bijlsma JW, et al. "Beating osteoARThritis": Development of a stepped care strategy to optimize utilization and timing of non-surgical treatment modalities for patients with hip or knee osteoarthritis. Clinical Rheumatology. 2011;**30**:1623-1629

[9] Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis and Cartilage. 2008;**16**:137-162

[10] American Academy of Orthopaedic Surgeons Board of Directors. Treatment of Osteoarthritis of the Knee Evidence-based Guideline. 2nd ed. 2013. Journal of the American Academy of Orthopaedic Surgeons. Sep 2013;**21**(9):571-576

[11] Centers for Disease Control and Prevention. Prevalence of doctor-diagnosed arthritis and possible arthritis—30 states, 2002. MMWR. Morbidity and Mortality Weekly Report. 2004;**53**:383-385

[12] Bitton R. The economic burden of osteoarthritis. The American Journal of Managed Care. 2009;**15**(Suppl 8): S230-S235

[13] Murphy L, Cisternas M, Yelin E, et al. Update: Direct and indirect costs of arthritis and other rheumatic conditions—United States, 1997. MMWR. Morbidity and Mortality Weekly Report. 2004;**53**(18):388-389

[14] Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis and Rheumatism. 2008;**59**:1207-1213

[15] Culliford DJ, Maskell J, Kiran A, et al. The lifetime risk of total hip and knee arthroplasty: Results from the UK general practice research database. Osteoarthritis and Cartilage. 2012;**20**:519-524

[16] Suri P, Morgenroth DC, Hunter DJ. Epidemiology of osteoarthritis and associated comorbidities.

**51**

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

[26] Fortier LA, Nixon AJ, Mohammed HO, et al. Altered biological activity of equine chondrocytes cultured in a three-dimensional fibrin matrix and supplemented with transforming growth factor beta-1. American Journal of Veterinary Research.

[27] Iqbal J, Dudhia J, Bird JL, et al. Age-related effects of TGF-b on proteoglycan synthesis in equine articular cartilage. Biochemical and Biophysical Research Communications.

[28] Frisbie DD, Sandler EA, Trotter GW, et al. Metabolic and fitogeni activities of insulin-like growth factor-1 in interleukin-1-conditioned

[29] Tung JT, Arnold CE, Alexander LH, et al. Evaluation of the influence of prostaglandin E2 on recombinant equine interleukin-1b-stimulated matrix metalloproteinases 1, 3, and 13 and tissue inhibitor of matrix metalloproteinase 1 expression in equine chondrocyte cultures. American

Journal of Veterinary Research.

[31] Brama PA, van den Boom R, DeGroott J, et al. PR Collagenase-1 (MMP-1) activity in equine synovial fluid: Influence of age, joint pathology, exercise and repeated arthrocentesis.

Equine Veterinary Journal.

[32] Platt D. Articular cartilage homeostasis and the role of growth factors and cytokines in regulating matrix composition. In: McIlwraith CW, Trotter GW, editors. Joint Disease in

2004;**36**(1):34-40

[30] Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: Role in arthritis. Frontiers in Bioscience.

1997;**58**(1):66-70

2000;**274**(2):467-471

equine cartilage. American Journal of Veterinary Research.

2000;**61**(4):436-441

2002;**63**(7):987-993

2006;**11**:529-543

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

Physical Medicine and Rehabilitation.

[17] De Filippis L, Gulli S, Caliri A, et al. Epidemiology and risk factors in osteoarthritis: Literature review data from "OASIS" study. Reumatismo.

[18] Lavernia CJ, Sierra RJ, Grieco FR. Osteonecrosis of the femoral head. The Journal of the American Academy of Orthopaedic Surgeons.

[19] Urbaniak JR, Jones JP Jr, editors. Osteonecrosis: Etiology, Diagnosis, and Treatment. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1997

[20] Pivec R, Johnson AJ, Harwin SF, Mont MA. Differentiation, diagnosis, and treatment of osteoarthritis, osteonecrosis, and rapidly progressive osteoarthritis. Orthopedics. 2013;**36**(2):118-125. DOI:

10.3928/01477447-20130122-04

WB Saunders; 1996. pp. 87-104

[24] Lozada C. Osteoarthritis in Medscape reference. 2012. Available at: http://emedicine.medscape.com/

[25] Prockop DJ. Heritable osteoarthritis: Diagnosis and possible modes of cell and gene therapy. Osteoarthritis and

article/330487-overview

Cartilage. 1994;**7**(4):364-366

[23] Bonnet DS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology.

2005;**44**(1):7-16

[21] Hinton R, Moody RL, Davis AW, et al. Osteoarthritis: Diagnosis and therapeutic considerations. American Family Physician. 2002;**65**(5):841-849

[22] Pool RR. Pathologic manifestations of joint disease in the athletic horse. In: McIlwraith CW, Trotter GW, editors. Joint Disease in the Horse. Philadelphia:

2012;**4**(Suppl 5):S10-S19

2004;**56**(3):169-184

1999;**7**(4):250-261

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*

Physical Medicine and Rehabilitation. 2012;**4**(Suppl 5):S10-S19

[17] De Filippis L, Gulli S, Caliri A, et al. Epidemiology and risk factors in osteoarthritis: Literature review data from "OASIS" study. Reumatismo. 2004;**56**(3):169-184

[18] Lavernia CJ, Sierra RJ, Grieco FR. Osteonecrosis of the femoral head. The Journal of the American Academy of Orthopaedic Surgeons. 1999;**7**(4):250-261

[19] Urbaniak JR, Jones JP Jr, editors. Osteonecrosis: Etiology, Diagnosis, and Treatment. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1997

[20] Pivec R, Johnson AJ, Harwin SF, Mont MA. Differentiation, diagnosis, and treatment of osteoarthritis, osteonecrosis, and rapidly progressive osteoarthritis. Orthopedics. 2013;**36**(2):118-125. DOI: 10.3928/01477447-20130122-04

[21] Hinton R, Moody RL, Davis AW, et al. Osteoarthritis: Diagnosis and therapeutic considerations. American Family Physician. 2002;**65**(5):841-849

[22] Pool RR. Pathologic manifestations of joint disease in the athletic horse. In: McIlwraith CW, Trotter GW, editors. Joint Disease in the Horse. Philadelphia: WB Saunders; 1996. pp. 87-104

[23] Bonnet DS, Walsh DA. Osteoarthritis, angiogenesis and inflammation. Rheumatology. 2005;**44**(1):7-16

[24] Lozada C. Osteoarthritis in Medscape reference. 2012. Available at: http://emedicine.medscape.com/ article/330487-overview

[25] Prockop DJ. Heritable osteoarthritis: Diagnosis and possible modes of cell and gene therapy. Osteoarthritis and Cartilage. 1994;**7**(4):364-366

[26] Fortier LA, Nixon AJ, Mohammed HO, et al. Altered biological activity of equine chondrocytes cultured in a three-dimensional fibrin matrix and supplemented with transforming growth factor beta-1. American Journal of Veterinary Research. 1997;**58**(1):66-70

[27] Iqbal J, Dudhia J, Bird JL, et al. Age-related effects of TGF-b on proteoglycan synthesis in equine articular cartilage. Biochemical and Biophysical Research Communications. 2000;**274**(2):467-471

[28] Frisbie DD, Sandler EA, Trotter GW, et al. Metabolic and fitogeni activities of insulin-like growth factor-1 in interleukin-1-conditioned equine cartilage. American Journal of Veterinary Research. 2000;**61**(4):436-441

[29] Tung JT, Arnold CE, Alexander LH, et al. Evaluation of the influence of prostaglandin E2 on recombinant equine interleukin-1b-stimulated matrix metalloproteinases 1, 3, and 13 and tissue inhibitor of matrix metalloproteinase 1 expression in equine chondrocyte cultures. American Journal of Veterinary Research. 2002;**63**(7):987-993

[30] Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: Role in arthritis. Frontiers in Bioscience. 2006;**11**:529-543

[31] Brama PA, van den Boom R, DeGroott J, et al. PR Collagenase-1 (MMP-1) activity in equine synovial fluid: Influence of age, joint pathology, exercise and repeated arthrocentesis. Equine Veterinary Journal. 2004;**36**(1):34-40

[32] Platt D. Articular cartilage homeostasis and the role of growth factors and cytokines in regulating matrix composition. In: McIlwraith CW, Trotter GW, editors. Joint Disease in

**50**

*Osteoarthritis Biomarkers and Treatments*

[1] Goodman S. Osteoarthritis. In: Yee A, Paget S, editors. Expert Guide to Rheumatology. Philadelphia, PA: American College of Physicians; 2005. [9] Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis and Cartilage.

[10] American Academy of Orthopaedic

Surgeons Board of Directors. Treatment of Osteoarthritis of the Knee Evidence-based Guideline. 2nd ed. 2013. Journal of the American Academy of Orthopaedic Surgeons. Sep

[11] Centers for Disease Control and Prevention. Prevalence of doctor-diagnosed arthritis and possible arthritis—30 states, 2002. MMWR. Morbidity and Mortality Weekly Report. 2004;**53**:383-385

[12] Bitton R. The economic burden of osteoarthritis. The American Journal of Managed Care. 2009;**15**(Suppl 8):

[13] Murphy L, Cisternas M, Yelin E, et al. Update: Direct and indirect costs of arthritis and other rheumatic conditions—United States, 1997. MMWR. Morbidity and Mortality Weekly Report. 2004;**53**(18):388-389

[14] Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis and Rheumatism. 2008;**59**:1207-1213

[15] Culliford DJ, Maskell J, Kiran A, et al. The lifetime risk of total hip and knee arthroplasty: Results from the UK general practice research database. Osteoarthritis and Cartilage.

[16] Suri P, Morgenroth DC, Hunter DJ. Epidemiology of osteoarthritis and associated comorbidities.

2012;**20**:519-524

2008;**16**:137-162

2013;**21**(9):571-576

S230-S235

[2] Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: An update with relevance for clinical practice. Lancet.

[3] DiCesare PE, Abramson S, Samuels J. Pathogenesis of osteoarthritis. In: Firestein GS, Kelley WN, editors. Kelley's Textbook of Rheumatology. 8th ed. Philadelphia, PA, Saunders Elsevier;

[4] Bateman JF. Genetic aspects of osteoarthritis. Seminars in Arthritis and Rheumatism. 2005;**34**(6 Suppl 2):15-18

[5] Ryder JJ, Garrison K, Song F, et al. Genetic associations in peripheral joint osteoarthritis and spinal degenerative

disease: A systematic review. Annals of the Rheumatic Diseases.

[6] Valdes AM, Spector TD. The genetic epidemiology of osteoarthritis. Current Opinion in Rheumatology.

[7] McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis and Cartilage.

[8] Smink AJ, van den Ende CH, Vliet Vlieland TP, Swierstra BA, Kortland JH, Bijlsma JW, et al. "Beating osteoARThritis": Development of a stepped care strategy to optimize utilization and timing of non-surgical treatment modalities for patients with hip or knee osteoarthritis. Clinical Rheumatology. 2011;**30**:1623-1629

2008;**67**(5):584-591

2010;**22**(2):139-143

2014;**22**:363-388

**References**

pp. 269-283

2009

2011;**377**:2115-2126

the Horse. Philadelphia: WB Saunders; 1996. pp. 29-40

[33] Loeser RF. Systemic and local regulation of articular cartilage metabolism: Where does leptin fit in the puzzle? Arthritis and Rheumatism. 2003;**48**(11):3009-3012

[34] Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JWJ, Dieppe P, et al. EULAR recommendations 2003: An evidence based medicine approach to the management of knee osteoarthritis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Annals of the Rheumatic Diseases. 2003;**62**:1145-1155

[35] Punzi L, Canesi B, Carrabba M, Cimmino MA, Frizziero L, Lapadula G, et al. Consensus italiana sulle raccomandazioni EULAR 2003 per il trattamento della gonartrosi. Reumatismo. 2004;**56**:190-201

[36] Bert JM, Bert TM. Nonoperative treatment of unicompartmental arthritis: From bracing to injection. Clinics in Sports Medicine. 2014;**33**(1):1-10

[37] Uthman I, Raynauld JP, Haraoui B. Intra-articular therapy in osteoarthritis. Postgraduate Medical Journal. 2003;**79**(934):449-453

[38] Douglas RJ. Corticosteroid injection into the osteoarthritic knee: Drug selection, dose, and injection frequency. International Journal of Clinical Practice. 2012;**66**(7):699-704

[39] McGarry JG, Daruwalla ZJ. The efficacy, accuracy and complications of corticosteroid injections of the knee joint. Knee Surgery, Sports Traumatology, Arthroscopy. 2011;**19**(10):1649-1654

[40] Altman RD, Manjoo A, Fierlinger A, Niazi F, Nicholls M. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: A systematic review. BMC Musculoskeletal Disorders. 2015;**16**:321

[41] HK V, Percival SS, Conrad BP, Seay AN, Montero C, Vincent KR. Hyaluronic acid (HA) viscosupplementation on synovial fluid inflammation in knee osteoarthritis: A pilot study. The Open Orthopaedics Journal. 2013;**7**:378-384

[42] Mazzucco L, Balbo V, Cattana E, Guaschino R, Borzini P. Not every PRP-gel is born equal. Evaluation of growth factor availability for tissues through four PRP-gel preparations: Fibrinet, RegenPRPKit, Plateltex and one manual procedure. Vox Sanguinis. 2009;**97**(02):110-118

[43] Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Medicine. 2003;**33**(05):381-394

[44] Staudenmaier R, Froelich K, Birner M, et al. Optimization of platelet isolation and extraction of autogenous TGF-beta in cartilage tissue engineering. Artificial Cells, Blood Substitutes, and Immobilization Biotechnology. 2009;**37**(06):265-272

[45] Paterson KL, Nicholls M, Bennell KL, Bates D. Intra-articular injection of photo-activated platelet-rich plasma in patients with knee osteoarthritis: A double-blind, randomized controlled pilot study. BMC Musculoskeletal Disorders. 2016;**17**(01):67. DOI: 10.1186/ s12891-016-0920-3

[46] Kavadar G, Demircioglu DT, Celik MY, Emre TY. Effectiveness of platelet-rich plasma in the treatment of moderate knee osteoarthritis: A randomized prospective study. Journal of Physical Therapy Science. 2015;**27**(12):3863-3867

[47] Smith PA. Intra-articular autologous conditioned plasma injections

**53**

May 31

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results*

[54] Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;**3**(4):e1886. https://doi. org/10.1371/journal.pone.0001886

[55] Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells

International. 2012;**2012**:812693. DOI: 10.1155/2012/812693. Epub 2012 Apr 12

[57] Bianchi F, Olivi E, Baldassarre M, Giannone FA, Laggetta M, Valente S, et al. Lipogems, a new modality of fat tissue handling to enhance tissue repair in chronic hind limb ischemia. CellR4.

[58] Tremolada C, Palmieri G, Ricordi C. Adipocyte transplantation and stem cells: Plastic surgery meets regenerative

medicine. Cell Transplantation.

[59] Klinger M, Lisa A, Klinger F, Giannasi S, Veronesi A, Banzatti B, et al. Regenerative approach to scars, ulcers and related problems with fat grafting. Clinics in Plastic Surgery. 2015;**42**(3):345-352. https://doi. org/10.1016/j.cps.2015.03.008

[60] Perdisa F, Gostyńska N, Roffi A, Filardo G, Marcacci M, Kon E. Adiposederived mesenchymal stem cells for the treatment of articular cartilage: A systematic review on preclinical and clinical evidence. Stem Cells

2010;**19**(10):1217-1223

2014;**2**(6):e1289

[56] Chen H, Lee MJ, Chen CH, Chuang SC, Chang LF, Ho ML, et al. Proliferation and differentiation potential of human adiposederived mesenchymal stem cells isolated from elderly patients with osteoporotic fractures. Journal of Cellular and Molecular Medicine. Mar, 2012;**16**(3):582-593. DOI: 10.1111/j.1582-4934.2011.01335.x

*DOI: http://dx.doi.org/10.5772/intechopen.82566*

provide safe and efficacious treatment for knee osteoarthritis: An FDA-

sanctioned, randomized, double-blind, placebocontrolled clinical trial. The American Journal of Sports Medicine.

[48] Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Plateletrich therapies for musculoskeletal soft tissue injuries. Cochrane Database of Systematic Reviews. 2014;**4**(04):CD010071. DOI: 10.1002/14651858.CD010071.pub2

[49] Grambart ST. Sports medicine and platelet-rich plasma: Nonsurgical therapy. Clinics in Podiatric Medicine and Surgery. 2015;**32**(01):99-107

[50] Duymus TM, Mutlu S, Dernek B, Komur B, Aydogmus S, Kesiktas FN. Choice of intra-articular injection in treatment of knee osteoarthritis: Platelet-rich plasma, hyaluronic acid or ozone options. Knee Surgery, Sports Traumatology, Arthroscopy.

[51] DeChellis DM, Cortazzo MH. Regenerative medicine in the field of pain medicine: Prolotherapy, platelet-rich plasma therapy, and stem cell therapy—Theory and evidence. Techniques in Regional Anesthesia and Pain Management. 2011;**15**(02):74-80

[52] Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Experimental & Molecular Medicine. 2013;**45**:e54. DOI: 10.1038/emm.2013.94

[53] Doorn J, van de Peppel J, van Leeuwen JP, Groen N, van Blitterswijk CA, de Boer J. Proosteogenic trophic effects by PKA activation in human mesenchymal stromal cells. Biomaterials. Sep, 2011;**32**(26):6089-6098. DOI: 10.1016/j. biomaterials.2011.05.010. Epub 2011

2017;**25**(02):485-492

2016;**44**(04):884-891

*Fat Tissue's Graft in Osteoarthritis Treatment: Indications, Preparations, and Results DOI: http://dx.doi.org/10.5772/intechopen.82566*

provide safe and efficacious treatment for knee osteoarthritis: An FDAsanctioned, randomized, double-blind, placebocontrolled clinical trial. The American Journal of Sports Medicine. 2016;**44**(04):884-891

*Osteoarthritis Biomarkers and Treatments*

[33] Loeser RF. Systemic and local regulation of articular cartilage metabolism: Where does leptin fit in the puzzle? Arthritis and Rheumatism.

2003;**48**(11):3009-3012

Diseases. 2003;**62**:1145-1155

[35] Punzi L, Canesi B, Carrabba M, Cimmino MA, Frizziero L, Lapadula G, et al. Consensus italiana sulle raccomandazioni EULAR 2003 per il trattamento della gonartrosi. Reumatismo. 2004;**56**:190-201

[36] Bert JM, Bert TM. Nonoperative treatment of unicompartmental arthritis: From bracing to injection.

[37] Uthman I, Raynauld JP, Haraoui

osteoarthritis. Postgraduate Medical Journal. 2003;**79**(934):449-453

International Journal of Clinical Practice. 2012;**66**(7):699-704

[39] McGarry JG, Daruwalla ZJ. The efficacy, accuracy and complications of corticosteroid injections of the knee joint. Knee Surgery, Sports Traumatology, Arthroscopy. 2011;**19**(10):1649-1654

[40] Altman RD, Manjoo A, Fierlinger A, Niazi F, Nicholls M. The mechanism

[38] Douglas RJ. Corticosteroid injection into the osteoarthritic knee: Drug selection, dose, and injection frequency.

Clinics in Sports Medicine.

B. Intra-articular therapy in

2014;**33**(1):1-10

1996. pp. 29-40

the Horse. Philadelphia: WB Saunders;

of action for hyaluronic acid treatment in the osteoarthritic knee: A systematic review. BMC Musculoskeletal Disorders.

[41] HK V, Percival SS, Conrad BP, Seay AN, Montero C, Vincent KR. Hyaluronic acid (HA) viscosupplementation on synovial fluid inflammation in knee osteoarthritis: A pilot study. The Open Orthopaedics Journal. 2013;**7**:378-384

[42] Mazzucco L, Balbo V, Cattana E, Guaschino R, Borzini P. Not every PRP-gel is born equal. Evaluation of growth factor availability for tissues through four PRP-gel preparations: Fibrinet, RegenPRPKit, Plateltex and one manual procedure. Vox Sanguinis.

[43] Molloy T, Wang Y, Murrell G. The roles of growth factors in tendon and ligament healing. Sports Medicine.

[44] Staudenmaier R, Froelich K, Birner M, et al. Optimization of platelet isolation and extraction of autogenous TGF-beta in cartilage tissue engineering. Artificial Cells, Blood Substitutes, and Immobilization Biotechnology.

[45] Paterson KL, Nicholls M, Bennell KL, Bates D. Intra-articular injection of photo-activated platelet-rich plasma in patients with knee osteoarthritis: A double-blind, randomized controlled pilot study. BMC Musculoskeletal Disorders. 2016;**17**(01):67. DOI: 10.1186/

[46] Kavadar G, Demircioglu DT, Celik MY, Emre TY. Effectiveness of platelet-rich plasma in the treatment of moderate knee osteoarthritis: A randomized prospective study. Journal of Physical Therapy Science.

[47] Smith PA. Intra-articular autologous

2009;**97**(02):110-118

2003;**33**(05):381-394

2009;**37**(06):265-272

s12891-016-0920-3

2015;**27**(12):3863-3867

conditioned plasma injections

2015;**16**:321

[34] Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JWJ, Dieppe P, et al. EULAR recommendations 2003: An evidence based medicine approach to the management of knee osteoarthritis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Annals of the Rheumatic

**52**

[48] Moraes VY, Lenza M, Tamaoki MJ, Faloppa F, Belloti JC. Plateletrich therapies for musculoskeletal soft tissue injuries. Cochrane Database of Systematic Reviews. 2014;**4**(04):CD010071. DOI: 10.1002/14651858.CD010071.pub2

[49] Grambart ST. Sports medicine and platelet-rich plasma: Nonsurgical therapy. Clinics in Podiatric Medicine and Surgery. 2015;**32**(01):99-107

[50] Duymus TM, Mutlu S, Dernek B, Komur B, Aydogmus S, Kesiktas FN. Choice of intra-articular injection in treatment of knee osteoarthritis: Platelet-rich plasma, hyaluronic acid or ozone options. Knee Surgery, Sports Traumatology, Arthroscopy. 2017;**25**(02):485-492

[51] DeChellis DM, Cortazzo MH. Regenerative medicine in the field of pain medicine: Prolotherapy, platelet-rich plasma therapy, and stem cell therapy—Theory and evidence. Techniques in Regional Anesthesia and Pain Management. 2011;**15**(02):74-80

[52] Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Experimental & Molecular Medicine. 2013;**45**:e54. DOI: 10.1038/emm.2013.94

[53] Doorn J, van de Peppel J, van Leeuwen JP, Groen N, van Blitterswijk CA, de Boer J. Proosteogenic trophic effects by PKA activation in human mesenchymal stromal cells. Biomaterials. Sep, 2011;**32**(26):6089-6098. DOI: 10.1016/j. biomaterials.2011.05.010. Epub 2011 May 31

[54] Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One. 2008;**3**(4):e1886. https://doi. org/10.1371/journal.pone.0001886

[55] Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells International. 2012;**2012**:812693. DOI: 10.1155/2012/812693. Epub 2012 Apr 12

[56] Chen H, Lee MJ, Chen CH, Chuang SC, Chang LF, Ho ML, et al. Proliferation and differentiation potential of human adiposederived mesenchymal stem cells isolated from elderly patients with osteoporotic fractures. Journal of Cellular and Molecular Medicine. Mar, 2012;**16**(3):582-593. DOI: 10.1111/j.1582-4934.2011.01335.x

[57] Bianchi F, Olivi E, Baldassarre M, Giannone FA, Laggetta M, Valente S, et al. Lipogems, a new modality of fat tissue handling to enhance tissue repair in chronic hind limb ischemia. CellR4. 2014;**2**(6):e1289

[58] Tremolada C, Palmieri G, Ricordi C. Adipocyte transplantation and stem cells: Plastic surgery meets regenerative medicine. Cell Transplantation. 2010;**19**(10):1217-1223

[59] Klinger M, Lisa A, Klinger F, Giannasi S, Veronesi A, Banzatti B, et al. Regenerative approach to scars, ulcers and related problems with fat grafting. Clinics in Plastic Surgery. 2015;**42**(3):345-352. https://doi. org/10.1016/j.cps.2015.03.008

[60] Perdisa F, Gostyńska N, Roffi A, Filardo G, Marcacci M, Kon E. Adiposederived mesenchymal stem cells for the treatment of articular cartilage: A systematic review on preclinical and clinical evidence. Stem Cells

International. 2015. Article ID: 597652. https://doi.org/10.1155/2015/597652

[61] Goisis M, editor. Outpatient regenerative medicine. In: Fat Injection and PRP as Minor Officebased Procedures. 2019. DOI: 10.1007/978-3-319-44894-7

[62] Hattori H, Masuoka K, Sato M. Bone formation using human adipose tissue-derived stromal cells and a biodegradable scaffold. Journal of Biomedical Materials Research Part B: Applied Biomaterials. 2006;**76**:230-239

[63] Hattori H, Sato M, Masuoka K, et al. Osteogenic potential of human adipose tissue-derived stromal cells as an alternative stem cell source. Cells, Tissues, Organs. 2004;**178**:2-12

[64] Hattori H, Nogami Y, Tanaka T. Expansion and characterization of adipose tissue-derived stromal cells cultured with low serum medium. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2008;**87**:229-236

Section 3

Natural Treatments for

Osteoarthritis

55

[65] Masuoka K, Asazuma T, Hattori H. Tissue engineering of articular cartilage with autologous cultured adipose tissue-derived stromal cells using atelocollagen honeycomb-shaped scaffold with a membrane sealing in rabbits. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2006;**79**:25-34

Section 3
