Role of Cellular Responses in Periodontal Tissue Destruction

*Nam Cong-Nhat Huynh*

## **Abstract**

Periodontal tissue destruction is the deterioration of tooth-supporting components, particularly the periodontal ligament (PDL) and alveolar bone, resulting in gingival recession, root exposure, tooth mobility and drifting, and, finally, tooth loss. The breakdown of the epithelial barriers by infection or mechanical damage allows bacteria and their toxins to enter and stimulates the immune response. The bacteria cause periodontal damage via the cascade of the host reaction which is crucial in the destruction of the connective tissue around the tooth. The OPG/RANKL/RANK system is the key player in bone regulation of periodontal tissue and was controlled by both immune and non-immune cells. This knowledge has predicated the successfulness of implant and orthodontics treatments with the predictable healing and regeneration of the bone and supporting tissues surrounding the teeth.

**Keywords:** RANKL, OPG, RANK, osteoimmunology, periodontal destruction, periodontitis, bone resorption, inflammation, immune response

## **1. Introduction**

The periodontium is made up of four components: gingiva, alveolar bone, cementum, and periodontal ligament (PDL) (**Figure 1**) [1]. They differ in cellular composition, protein kinds and quantities, mineralization, metabolic activity, and disease susceptibility. Embryologically, the gingival component is produced from the pharyngeal arches' ectoderm and contains stratified squamous epithelium while PDL, cementum, and alveolar bone are produced from neuro-mesenchymal stem cells and contain connective tissues [2]. Periodontal destruction is initiated by bacterial agents (periodontitis) or mechanism stimuli (such as orthodontic force or dental trauma). However, host response plays a very important role in the demolition of the connective tissue around the tooth. In this chapter, we concisely discussed the cellular responses, including immune and non-immune cells to the destruction of periodontal tissue, and how we applied the knowledge in dental practice.

## **2. Periodontal tissues destruction**

The components of periodontal tissue can be divided into hard tissue (cementum and alveolar bone) and soft tissue (gingiva and PDL). The anchors to which the

### **Figure 1.**

*Periodontium is made up of four components: gingiva, alveolar bone, cementum, and periodontal ligament (PDL). Oral epithelium (OE): is the epithelium that exposes to the surface of the mouth. Sulcular epithelium (SE): is the epithelium that contacts the surface of the tooth. Paroxizmalnaya form epithelium (JE): the epithelium which connects the gingiva to the tooth. OE, SE, and JE are keratinized tissue while alveolar mucosa is non-keratinized. Created with BioRender.com.*

fibrous PDL binds the tooth into the skeleton are the two mineralized tissues, cementum and alveolar bone [3]. The gingiva is the periodontium's covering tissue, providing immediate protection for the underlying tissues and extra tooth attachment. The cementum is the calcified avascular mesenchymal tissue that forms the anatomic root's outer layer. The periodontium's primary roles include protecting teeth, nerves, and blood vessels from mechanical stresses, attaching teeth to the bone, and transmitting occlusal forces and sensibility to stimuli such as temperature and pain [4].

Periodontitis (PD) is a common illness that can lead to tooth loss and causes a slew of problems for physicians. Periodontitis is caused by inflammation of the toothsupporting tissues, which results in the gradual loss of PDL and alveolar bones [5]. Periodontal disease is a collection of chronic inflammatory diseases that affect the gingiva, bone, and ligament (the connective tissue collagen fibers that bind a tooth to the alveolar bone) that support the teeth [6]. Chronic periodontitis occurs when untreated gingivitis progresses to the loss of gingiva, bone, and ligament, resulting in the deep periodontal 'pockets' that are a characteristic of the condition and can eventually lead to tooth loss. Periodontal disease can aggravate inflammatory illnesses, such as diabetes and atherosclerosis by increasing the body's total inflammatory load.

On the other hand, apical periodontitis (AP) is an infection that causes inflammation and destruction of the periradicular tissues. It happens as a result of a series of assaults on the tooth pulp, such as infection, physical and iatrogenic trauma, endodontic therapy, and the destructive effects of root canal filling materials [7]. Then, the host mounts a slew of defenses, including various cell types, intercellular messengers, antibodies, and effector chemicals. Microbial factors and host defense forces interact with, battle with, and destroy much of the periapical tissue, resulting in the

### *Role of Cellular Responses in Periodontal Tissue Destruction DOI: http://dx.doi.org/10.5772/intechopen.106645*

production of several types of AP lesions, most often reactive granulomas and cysts, with simultaneous bone resorption around the roots of impacted teeth.

Periodontitis or dental trauma can result in periodontal tissue destruction. It is the destruction of the tooth-supporting structures especially the PDL, and alveolar bone leading to the recession of the marginal gingiva, root exposure, tooth mobility and drifting, and, eventually, tooth loss. They are the results of chronic periodontitis with host defense response, tissue inflammation, and bone destruction in response to bacterial aggression [8]. Especially, the receptor activator of nuclear factor – (KB) ligand (RANKL) is a member of the TNF cytokine family encoded by the gene TNFSF11. It expresses in a membrane-bound protein or secreted forms and plays an important role in bone resorption including periodontal bone destruction via cellular and immune responses under the term the cross-talk between bone biology and immunology - osteoimmunology [9, 10].

## **3. Cellular responses in periodontal tissue destruction**

### **3.1 Immune cell responses**

The first physical barrier that is against infection from bacterial invasion is the periodontal epithelium. The epithelial barriers prevent pathogenic invasion and protect the periodontal tissues. The cells are involved in an active role in the innate host defense as well as further acquired immune responses. When the pathogens overcome the fence, they cause inflammation and destruction of the connective tissue, with subsequent bone loss and tooth loss. In periodontal tissues, cytokines are produced by fibroblasts, endothelial cells, macrophages, osteoclasts, epithelial cells, and leukocytes. By those mediators, osteoclasts will be differentiated and accumulated to the injury (**Figure 2**) [12].

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. They produce a number of mediators of signaling to induce osteoclastogenesis, such as IL-1, -6, and -17; RANKL; and TNF-α. The differentiation of osteoclast is mainly regulated by RANKL and macrophage-colony stimulating factor (M-CSF). Both of these factors are secreted by immune cells and osteoblasts, odontoblasts, osteoclasts, and other cells in the PDL during alveolar bone resorption [13]. On the other hand, osteoprotegerin (OPG) is a member of the TNF receptor superfamily that prevents osteoclast differentiation, as well as its resorptive function, and stimulates osteoclast apoptosis. It is found in PDL cells and osteoblasts while Receptor activator of nuclear factor κ B (RANK) is detected in osteoclasts and osteoclast precursors. In normal bone remodeling and a variety of pathologic circumstances, RANKL/RANK signaling directs the generation of multinucleated osteoclasts from their progenitors, as well as their activation and survival. By attaching to RANKL and inhibiting it from connecting to its receptor, RANK, OPG protects the skeleton from excessive bone resorption. As a result, the RANKL/OPG ratio is a key predictor of bone mass and skeletal integrity [14].

Early, Baker et al. [15] found that following *Porphyromonas gingivalis* infection in periodontal disease, CD4+ T cells and their proinflammatory cytokines are important effectors of bone destruction as an adaptive immune response [15]. Directly, CD4+ T cells are the primary cells responsible for the increased levels of RANKL in chronic periodontitis patients contributing to the molecular local imbalance that

### **Figure 2.**

*The mechanisms involved in periodontal tissue destruction. The breakdown of the epithelial barriers by infection or mechanical damage allows bacteria and their toxins to enter and stimulates the immune response. The OPG/RANKL/RANK system plays a central role in regulating bone destruction in periodontal tissue. RANKL binds to the RANK receptor on osteoclast precursor to activate osteoclast while OPG neutralizes this interaction to inhibit osteoclastogenesis. RANKL was main produced by periodontal stromal cells, such as gingival fibroblasts, PDL cells, cementoblasts, osteoblasts, and especially osteocytes as well as immune cells, such as T cells and B cells. T cells communicate with other cells, such as stromal cells, macrophages, and dendritic cells via IL-17, IL-6, and IL-23 to regulate RANKL/OPG signaling resulting in bone destruction and tooth loss and resolution of infection and inflammation [9, 11]. Created with BioRender.com.*

results in periodontitis-induced alveolar bone resorption [16]. Besides the ability to support osteoclastogenesis directly, T lymphocytes secrete IL-1, IL-6, and IL-17 which can stimulate RANKL expression. The cells also inhibit osteoclast formation by a number of inhibitory molecules such as IL-4, -10, and -13 … and IFN-γ [17]. Horwood 2001 [18] inhibited osteoclast formation in cocultures of rat and human cells treated with M-CSF and RANKL by IL-12 and IL-18. When they were administered at synergistically low doses both GM-CSF and IFN-γ were secreted. T helper cells also play role in determining the effect of the T lymphocytes' immune responses against periodontal diseases. Bainbridge et al. 2010 [19] tested the capacity of some *P. gingivalis* strains to induce gingival inflammation, immune responses, and alveolar bone resorption of periodontal disease. They found that these certain strains can induce significant systemic levels of IgG and isotypes IgG1, IgG2a, and IgG2b, indicating the involvement of both two types of T helper cell responses to infection.

In the bone resorption lesion of periodontal disease, regulatory T cell (Treg, FoxP3 + CD25+) was diminished and associated with the increased RANKL+ T cells [20].

### *Role of Cellular Responses in Periodontal Tissue Destruction DOI: http://dx.doi.org/10.5772/intechopen.106645*

Using animal models, Treg recruiting in periodontal tissue can inhibit periodontitis, however, Treg's function might be suppressed [21]. Intriguingly, under inflammatory conditions, several Tregs can convert into Th17 cells called exFoxp3Th17 cells, which induce strongly osteoclastogenesis and bone destruction via IL-17 production [22]. These cells are also found in periodontal lesions in response to the oral commensal bacteria and play a central role in periodontal inflammation [23].

It was known that B cells and plasma cells are also able to produce RANKL to induce osteoclastogenesis [24, 25]. However, there was little evidence of the role of B cells in osteoclastogenesis. In the absence of T lymphocytes, *Actinobacillus actinomycetemcomitans*-responsive B lymphocytes can lead to accelerate periodontal bone resorption via the up-regulation of RANKL [26, 27]. In brief, bacterial antigenspecific T and B lymphocytes play a key role in RANKL- mediated bone loss in periodontal tissue destruction [24].

### **3.2 Non-immune cell responses**

Regarding these oral pathogens, in PDL cells, *P. gingivalis* and/or nicotine activation increased reactive oxygen species (ROS) and superoxide production indicating oxidative stress [28]. It was confirmed clinically in the saliva of patients with chronic periodontitis [29, 30]. In gingival fibroblasts, high concentrations of saline (NaCl) inhibited cell migration but not proliferation [31]. These findings highlighted the susceptibility of these periodontal fibroblasts under oral stimulating factors. Injury to the periapical tissue can damage periodontal cells (gingival fibroblasts, PDL cells, cementoblasts), resulting in the production of cementoclasts/osteoclasts locally. *P. gingivalis* upregulated the RANKL expression in gingival fibroblasts and PDL cells, denoting enhanced osteoclastogenesis [32].

We previously separated cementoblasts from human third molars and cocultivating them with mononuclear blood cells. Both osteoclast development and resorptive activity were studied in the absence and presence of IL-1. Cementoblasts could initiate osteoclastogenesis via RANKL production, which is heavily influenced by IL-1β explaining why osteoclasts can arise around the root of teeth [33]. RANKL was also produced primarily by osteocytes during the alveolar bone remodeling of the orthodontic tooth movement process. Using a newly developed approach for isolating periodontal tissue component cells from the alveolar bone, Shoji-Matsunaga et al. discovered that osteocytes expressed far more RANKL than other periodontal tissue cells [34]. The decrease of orthodontic tooth movement in mice particularly missing RANKL in osteocytes demonstrated the crucial function of osteocyte-derived RANKL. The study highlighted the critical involvement of osteocyte-derived RANKL in alveolar bone remodeling, laying the groundwork for orthodontic force-mediated bone resorption.

### **3.3 Pro-inflammatory molecule responses**

Pro-inflammatory molecules including chemokines, interleukins, and TNF (Tumor Necrosis Factors) were secreted by immune and stromal cells during the inflammation and bone resorption of periodontal tissue destruction. Chemokines are chemotactic cytokines that stimulate the recruitment of inflammatory cells. Chemokines have a role in osteoclastogenesis by inducing the differentiation of osteoclasts, they also affect osteoclast functions/properties [35]. In this way, chemokines can affect periodontal bone loss by recruiting neutrophils to fight against bacteria. Yu et al. [36] use *P. gingivalis* in CXCR2-deficient mice, a type of chemokine receptor. The result showed that knockout mice were highly susceptible to alveolar bone loss. These mice also suggested a role for chemokines in maintaining normal bone homeostasis.

Interleukins are a group of cytokines that are expressed by leukocytes and function in the immune system. Many studies in human and animal patterns have indicated the mediating bone loss stimulated by periodontal pathogens. Delima [17] investigated the role of IL-1 in periodontal disease in monkeys by using an inhibitor. The results indicate that inhibition of IL-1 significantly reduces inflammation, connective tissue attachment loss, and bone resorption. Especially, the transgenic mice that overexpress a form of IL-1α in the oral mucosal epithelium develop a syndrome that possesses all of the major features of periodontal disease, including epithelial proliferation and apical migration, loss of attachment, and destruction of cementum and alveolar bone [37]. Using antibiotics did not reduce the disease, giving the role of IL-1 in mediating in promoting the destruction of the periodontium. However, other types of IL seem to reduce bone loss and symptoms of disease in the periodontium. For example, according to Shaker 2012 [38], the IL-11 concentration was significantly higher in control and chronic periodontitis groups in comparison to aggressive periodontitis groups.

Curiously, studies reported the opposing roles of IL-17 in periodontal bone resorption, especially with rheumatoid arthritis (RA) condition. Th17 cells produce mainly IL-17 leading to bone destruction in RA by mediating the osteoclastogenesis process [38, 39]. However, inflammatory mediators, including chemokines, cytokines, prostaglandin E2, and nitric oxide that IL-17 recruited in RA conditions have antibacterial properties that lead to bone protection in the context of periodontal infection. Yu et al. [36] examined IL-17's role in inflammatory bone loss induced by *P. gingivalis* in IL-17–deficient mice in an autoimmune arthritis model. These animals had increased periodontal bone degradation, indicating that IL-17 has a bone-protective effect.

TNF refers to a group of cytokines that can cause cell death. In this family, TNF-α has various functions, such as cytolysis of some specific cells, cachexia, pyrogen, cell proliferation, and differentiation in some cases. It seems to be that reducing the level of TNF-α in the body leads to reduce bone loss, however, it will increase the number of bacteria in the lesion since the lessen immune response. Garlet et al. [40] examined how TNF-α modulates the periodontal disease by *A. actinomycetemcomitans* in TNF-α receptor-deficient mice. These mice had less severe periodontitis with less alveolar bone loss and inflammatory reaction. However, the higher level of bacteria compares with the wild-type group.

## **4. Relation in dental practice**

Implants, orthodontics, and other areas of maxillofacial dentistry are more or less based on the predictable repair and regeneration of the bone and supporting tissues around the teeth. In the field of implantology, the process of bone repair and regeneration (osteogenesis) plays an important role in determining the success of treatment. Bone integration includes the initial stages of tissue response, peri-implant osteogenesis, and peri-implant bone remodeling, resulting in new bone formation on the implant surface. Composition, implant design, and surface treatment affect bone integration. Other factors include systemic condition, surgical technique, adequate healing time, and load-bearing properties. In dental implants, bone and implant integrate directly (**Figure 3**). There are no PDL and Sharpey's fibers that help to absorb

## *Role of Cellular Responses in Periodontal Tissue Destruction DOI: http://dx.doi.org/10.5772/intechopen.106645*

force and micro trauma. Instead, osteoblasts are attached to the mineralized collagen framework, forming a dense, mineralized area directly on the implant surface. The distance from the bone to the implant surface takes place in a continuous process of bone regeneration in response to stress and mechanical force over time. The cavity containing osteoclasts, osteoblasts, mesenchymal cells, and blood vessels is always present adjacent to the implant surface [41, 42]. Excessive micro-motion in healing leads to tension and torsion forces, stimulating the formation of a fibrin membrane around the implant, and displacing the bone-implant interface. This phenomenon loosens the implant, inhibiting bone integration.

Using the bone repair and regeneration processes to accelerate tooth movement in orthodontics can significantly reduce treatment time and harmful effects. The ability to move teeth is mainly determined by the regeneration of periodontal tissue, under the regulation of molecular mechanisms by the response of cells in the alveolar bone and PDL. Fluid shear stress that PDL cells are constantly subjected to, is a form of mechanical loading on the cell level. Under compression, the fluids are forced through the voids and are relocated either to adjacent zones of the PDL or driven into the neighboring alveolar bone. This fluid movement creates the type of mechanical

### **Figure 3.**

*The anchor of a dental implant in the alveolar bone directly by the osteointegration without the PDL and Sharpey's fibers in comparison to the real teeth (Figure 1). Note that there was also no connective tissue connection between the implant and the gingiva. Created with BioRender.com.*

loading known as fluid shear stress [43]. This force appears during the mastication, speech, and orthodontic procedure. By their arrangement and structure, fibers of PDL can absorb forces that are harmful to teeth and surrounding apparatus. However, excessing the endured limitation of PDL (by duration and/or magnitude), PDL can respond to the compression by stimulating many compartments. By using mechanical stress (light orthodontic application) to activate the fluid shear stress response in PDL cells, Yarmolyuk 2012 [44] showed that it could alleviate the compromised periodontal status via down-regulation of TLR4.

Similar to the inflammation response triggered by bacteria, mechanical forces also cause increased cytokine secretion by PDL cells. By using an orthodontic model which can mimic real situations, many studies have proven that IL-1β, IL-6, and TNF-α have been revealed in the compression side of teeth [45]. In the results of this elevation, the OPG/RANKL/RANK system will function leading to bone remodeling. Depending on the kind of force and its magnitude, the bone will be resorbed or formed prominently (**Figure 4**).

Interestingly, Diercke et al. [46] indicated that static compressive forces significantly induced the expression of ephrin-A2, while the expression of ephrin -B2 was significantly down-regulated in PDL. Although these coupling factors (Ephrin and eph receptor) have been defined as osteoclast-derived molecules that induce

### **Figure 4.**

*Orthodontics force induces periodontal and bone tissue remodeling. Mechanical stress applied to a tooth can destruct periodontal and bone tissue through the RANKL/RANK/OPG system. At the site of compression, periodontal tissue cells such as PDL cells, cementoblasts, osteoblasts, and osteocytes of alveolar bone can produce RANKL to active osteoclast via RANK leading to bone resorption. On the opposite side of the tooth where OPG will be produced increasingly by stromal cells to inhibit osteoclastogenesis leading to more bone formation. The application of too strong orthodontics force will enhance uncontrolled osteoclastogenesis/cementoclastogenesis leading to tooth's root resorption (external resorption) and periodontal tissue destruction permanently. Created with BioRender.com.*

osteoblastic bone formation. The more ephrin-A2, the more osteoclast, while reducing ephrin-B2 will reduce osteoblast formation [47].

Low-level lasers can also accelerate tooth migration, according to human and animal studies [48–52]. However, some studies suggest that low-level lasers do not accelerate tooth migration but also slow it down [53]. This difference may be explained by different treatment regimens including laser wavelength, radiation dose, location, and frequency. Several studies have reported that low-level lasers stimulate bone regeneration by increasing the number and function of osteoblasts and osteoclasts as well as markers, such as matrix metalloproteinase-9, cathepsin K, integrin [50], and the RANK/RANKL/OPG system [51, 54] at periodontal tissue. More research is needed to find the most effective regimen to extend its effectiveness.

## **5. Conclusions**

The imbalance between bone resorption and formation leads to the loss of bone and PDL. This process is regulated by inflammatory infiltration followed by a dozen of factors, such as bacterial products, cytokines, chemokines, and complements from surrounding cells and blood vessels. Using our knowledge of periodontal tissue destruction, bone repair, and regeneration mechanisms, and the factors that influence them help us to better understand the molecular mechanisms, explain phenomena and applications, and develop approaches to new treatments, thereby helping to achieve optimal treatment results, and minimizing complications for patients.

## **Acknowledgements**

The author thanks the Faculty of Odonto-Stomatology, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam for supporting this chapter.

## **Conflict of interest**

The author declares that there is no conflict of interest regarding the publication of this chapter.

*Periodontology - New Insights*

## **Author details**

Nam Cong-Nhat Huynh Faculty of Odonto-Stomatology, Laboratory of Prosthodontics, Laboratory of Oral-Maxillofacial Biology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam

\*Address all correspondence to: namhuynh@ump.edu.vn; huynhcongnhatnam@gmail.com

© 2022 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.

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## **Chapter 7**
