**3. Secondary osteoarthritis**

This type of OA is caused by other factors or disease, but the resulting pathological changes are the same as for primary OA.

Leading causes of secondary Osteoarthritis:


According to Creamer *et al.* [12], Knee Osteoarthritis (OA) is a significant cause of disability, particularly in older people. The factors determining disability remain unclear. A study was conducted to assess the impact of clinical and psychosocial variables on function in knee Osteoarthritis and to develop models to account for observed variance in self-reported disability. It was conducted that function in symptomatic knee Osteoarthritis is determined more by pain and obesity than by structural changes as seen on plain X-ray. Hunter and Felson [13] said that Osteoarthritis had been known believed to be a disease of articular cartilage since ages, but the current concept is entirely different. Hunter and Felson explained that OA is a structural and functional impairment of synovial joints resulting in a range

**229**

*Genetics in Osteoarthritis Knee*

causes secondary OA [14].

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

ligaments, periarticular muscle, capsule and synovium.

2% of the United States gross domestic product [21].

of disease. OA entails the whole joint including the subchondral bone, menisci,

Osteoarthritis (OA) is a chronic degenerative disorder of multifactorial etiology characterized by loss of articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis and range of biochemical and morphological alterations of the synovial membrane and joint capsule. It may be either Primary Osteoarthritis or Secondary Osteoarthritis. Primary OA is mostly related to aging. It can present as localized, generalized or as erosive Osteoarthritis. Another disease or condition

Osteoarthritis (OA) is a disease of the musculoskeletal system that primarily involves the joints of the knee, hip, spine, hand and foot. OA is estimated to affect 40% of people >70 years of age [15], making it more prevalent than any other form of arthritis [16]. The Framingham Knee Osteoarthritis study suggests that knee osteoarthritis increases in prevalence throughout the elderly, more so in women than in men [17]. Females are found to have more severe OA, more number of joints are involved, and have more symptoms and increased hand and knee OA [18]. Osteoarthritis (OA) is the most common cause of musculoskeletal disability related to aging and is characterized by late-onset degeneration of articular cartilage [19]. OA is one of the leading causes of disability and dysfunction in the elderly population [20]; it has been estimated that the total cost for arthritis, including OA, is over

**Prevalence of OA:** Osteoarthritis (OA) is the second most common rheumatological problem and is the most frequent joint disease with a prevalence of 80% in the population having radiographic evidence. About 60% of radiographically evidenced subjects are symptomatic [22]. In India, more than 41.1% of the population suffers from Osteoarthritis beyond the age of 50 years [23]. This is the most common cause of locomotor disability in the elderly [24]. More than 20 million people are affected with OA in the United States, including 10% of adults of age 50 years. It has been estimated that 2% of women and 1.4% of men develop radiographic OA per year, but approx half of these individual show symptoms [19]. **Etiology of OA:** OA is a multifactorial disease with both genetic and environmental determinants, and all cases are probably affected by both, with a continuous distribution between the extremes of genetic or predominantly environmental causes [15]. The pathophysiology of OA is complex and do not comprehend with its clinical feature. The disease is rare before the age of 40 years but frequency increases with age as large no. of individual with ≥70 years demonstrate radiographic evidence of OA in some joints. All cases are probably affected by both genetics and environment, with a continuous distribution between the extremes of

predominantly genetic or predominantly environmental causes [15].

**Role of genes in OA:** Role of genetics is emerging as an important etiological factor in recent times. More than 65 genes are associated with knee osteoarthritis (KOA) in different populations, and Indian population candidate genes like CALM-1 [25], VDR gene polymorphism [26], GDF-5 [22], SMAD-3, BMP-5, CCL2, COL2A1 [27] and COL2A1, CRTL1 [28] are associated with KOA. In recent years many studies have been conducted on KOA to investigate its association with SNPs. Genome-Wide Association Stu is performed on a large scale to identify the role of different loci in the development of the disease depending on the number of variants used. To date, more than ten loci (LSP1P3, GDF5, CHST11, FTO, GNL3, ASTN2, SENP6, PTHLH, TP63, CDC5L and CHST11) have been found associated with KOA through GWAS in European, Asian and Caucasians populations [29, 30]. Candidate gene studies have been responsible for identifying several susceptible loci for OA. GDF5, ASPN, FRZB and PTGS2 are few other genes which have been identified this way. These genes

#### *Genetics in Osteoarthritis Knee DOI: http://dx.doi.org/10.5772/intechopen.93890*

of disease. OA entails the whole joint including the subchondral bone, menisci, ligaments, periarticular muscle, capsule and synovium.

Osteoarthritis (OA) is a chronic degenerative disorder of multifactorial etiology characterized by loss of articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis and range of biochemical and morphological alterations of the synovial membrane and joint capsule. It may be either Primary Osteoarthritis or Secondary Osteoarthritis. Primary OA is mostly related to aging. It can present as localized, generalized or as erosive Osteoarthritis. Another disease or condition causes secondary OA [14].

Osteoarthritis (OA) is a disease of the musculoskeletal system that primarily involves the joints of the knee, hip, spine, hand and foot. OA is estimated to affect 40% of people >70 years of age [15], making it more prevalent than any other form of arthritis [16]. The Framingham Knee Osteoarthritis study suggests that knee osteoarthritis increases in prevalence throughout the elderly, more so in women than in men [17]. Females are found to have more severe OA, more number of joints are involved, and have more symptoms and increased hand and knee OA [18]. Osteoarthritis (OA) is the most common cause of musculoskeletal disability related to aging and is characterized by late-onset degeneration of articular cartilage [19]. OA is one of the leading causes of disability and dysfunction in the elderly population [20]; it has been estimated that the total cost for arthritis, including OA, is over 2% of the United States gross domestic product [21].

**Prevalence of OA:** Osteoarthritis (OA) is the second most common rheumatological problem and is the most frequent joint disease with a prevalence of 80% in the population having radiographic evidence. About 60% of radiographically evidenced subjects are symptomatic [22]. In India, more than 41.1% of the population suffers from Osteoarthritis beyond the age of 50 years [23]. This is the most common cause of locomotor disability in the elderly [24]. More than 20 million people are affected with OA in the United States, including 10% of adults of age 50 years. It has been estimated that 2% of women and 1.4% of men develop radiographic OA per year, but approx half of these individual show symptoms [19].

**Etiology of OA:** OA is a multifactorial disease with both genetic and environmental determinants, and all cases are probably affected by both, with a continuous distribution between the extremes of genetic or predominantly environmental causes [15]. The pathophysiology of OA is complex and do not comprehend with its clinical feature. The disease is rare before the age of 40 years but frequency increases with age as large no. of individual with ≥70 years demonstrate radiographic evidence of OA in some joints. All cases are probably affected by both genetics and environment, with a continuous distribution between the extremes of predominantly genetic or predominantly environmental causes [15].

**Role of genes in OA:** Role of genetics is emerging as an important etiological factor in recent times. More than 65 genes are associated with knee osteoarthritis (KOA) in different populations, and Indian population candidate genes like CALM-1 [25], VDR gene polymorphism [26], GDF-5 [22], SMAD-3, BMP-5, CCL2, COL2A1 [27] and COL2A1, CRTL1 [28] are associated with KOA. In recent years many studies have been conducted on KOA to investigate its association with SNPs. Genome-Wide Association Stu is performed on a large scale to identify the role of different loci in the development of the disease depending on the number of variants used. To date, more than ten loci (LSP1P3, GDF5, CHST11, FTO, GNL3, ASTN2, SENP6, PTHLH, TP63, CDC5L and CHST11) have been found associated with KOA through GWAS in European, Asian and Caucasians populations [29, 30]. Candidate gene studies have been responsible for identifying several susceptible loci for OA. GDF5, ASPN, FRZB and PTGS2 are few other genes which have been identified this way. These genes

continue to be the subject of functional studies and further genetic replication in independent populations [31–36].

Valdev et al. [37] reported an association between an amino acid variant in the TRPV1 gene and risk of symptomatic KOA for the first time. This amino acid has been implicated in pain sensitivity previously. The observation that the genotype implicated in lower pain sensitivity is significantly associated with a lower risk of painful OA. After adjustment for confounding variables (age, sex, BMI and radiographic severity) the difference between symptomatic and asymptomatic OA also achieves statistical significance.

Knee OA subjects showed individual characteristics in their expression of PBMC gene. A set of 173 genes was identified to diagnose Knee OA cases. The sensitivity and specificity were 89% and 76% respectively [38]. Besides, they observed that patients with symptomatic KOA could be categorized into two distinct groups based on the level of inflammatory gene expression (e.g., IL-1β, IL-8, COX-2). The differential overexpression of these inflammatory genes in KOA subclasses was validated using qPCR (*P* < 0.0001) in 2 cohorts from NYUHJD and one cohort from Duke University.

Yerges Armstrong et al. [39] identified four SNPs significantly associated with radiographic KOA. The strongest signal (p = 0.0009) maps to 12q3, which contains a gene coding for SP7. Additional loci map to 7p14.1 (TXNDC3), 11q13.2 (LRP5) and 11p14.1 (LIN7C). The allele associated with higher BMD was also associated with higher odds of KOA in all four loci. This meta-analysis demonstrated that several GWAS identified BMD SNPs are nominally associated with prevalent radiographic KOA and further supports the hypothesis that BMD or its determinants may be a risk factor contributing to OA development.

A study by Shi-Xing Luo et al. [40] on IL-16 showed a significant association of SNP rs4778889 with altered gene expression levels as well as two other SNPs (rs11556218 and rs4072111). The latter two SNPs are located in an exon region, and their single nucleotide change results in an amino acid substitution. This was the first study to investigate the association of IL16 polymorphism with KOA risk, and a significant effect was observed IL16 rs1155218. Polymorphism represented an Asn to Lys substitution in exon 6 of the gene. It was mentioned that individual with rs11549465 C allele was at lower risk to develop the disease than those with T allele. Javier Fernández-Torres et al. [41] found that the SNP rs11549465 located in the exon 12 within the HIF1A gene was associated with KOA in Mexican patients. Their results showed that the presence of the *CC* homozygous variant or *C* allele represents potential risk factors for development of KOA. On the contrary to this, they detected that the heterozygous variant of CT or *T* allele of the rs11549465 polymorphism of the HIF1A gene (in comparison with the homozygous carriers) play a protective role against the disease.

Rui Zhang et al. [32] demonstrated that SNP rs143383 of GDF5 is a compelling risk factor for both knees and hand OA and provide further support for GDF5 in etiology of OA. A recent study by Kwo Wei Ho et al. [42] suggested that the COL11A2, a collagen-encoding gene, may play a role in pain sensitization after the development of OA. In a case-control study, Haohuan Li et al. [43] investigated the association between EN1 rs4144782 and susceptibility to KOA in a Chinese population. A significant association of SNP was observed with increased risk of KOA. The results reconfirmed the close connection between BMD and OA.

**Indian scenario:** Besides our studies, not much work has been done on the association of SNPs in the Indian population. Studies published from our laboratory on genetic polymorphism in KOA demonstrated an association of BMP5, CCL2, COL2A1, IL1B, SMAD3, GDF5, ESR-α, CALM1 and COMP genes with the development of KOA. Background of these genes is given below.

**231**

*Genetics in Osteoarthritis Knee*

traits [52].

skeletal tissue [58].

*DOI: http://dx.doi.org/10.5772/intechopen.93890*

**4. Bone morphogenic protein (BMP5) gene**

BMP5 is a member of the TGF-β superfamily of secreted proteins whose family members are involved in synovial joint development and joint tissue homeostasis [44]. Hahn *et al.* [45] reported that BMP5 was found on human chromosome 6p12.1. BMPs were originated as protagonists of bone formation and growth. They have a major role in morphogenesis of a variety of vertebrate tissues and organs. They stimulate all proliferation and matrix synthesis for differentiation of chondrocytes. BMP5, in particulate, are known to regulate ovarian development [8, 46], cardiac development [47], and limb bud development [48] with a well-defined role in the differentiation of chondrocytes through the promotion of cell proliferation and matrix synthesis [49, 50]. Southam *et al*. [51] found that Polymorphisms located within the transcribed region of *BMP5* and its proximal promoter had previously been excluded for association with OA. Nevertheless, there is increasing evidence; however, that polymorphisms in regulatory elements involved in gene transcription play an important role in conferring susceptibility to complex disease

The studies carried out in multiple organisms demonstrated its role in the regulation of various episode of embryonic development which includes dorsal-ventral and left-right axis formation, mesenchymal-epithelial interactions, and differentiation of many specific tissues including lung, gut, kidney, hair, teeth, cartilage, and bone [7]. BMPs can trigger the entire process of cartilage and bone formation when implanted at ectopic sites in adult animals [53] and are usually expressed in and around early cartilage and bone precursors during embryonic development [54–57]. Moreover, mutations in different BMP genes block the formation of particular skeletal features, showing that BMPs are also required for the normal formation of

BMP1 is a protease which takes part in the maturation of fibrillar collagens whereas the other BMPs are secreted molecules of TGF-beta family [59, 60]. BMPs influence the normal development and repair of the synovial joint; therefore alterations in the activity of these molecules could affect the arthritic phenotype [61, 62]. Using genetic association analysis, we have tested BMP5 as the chromosome 6 OA susceptibility gene. Zuzarte-Luis *et al*. [63] provided evidence for a role of this BMP member in the development of limb autopodium through the activation of Smad proteins and MAPK p38. Previous studies demonstrate that secreted signaling molecules in the bone morphogenetic protein (BMP) family play a vital role in both formation and repair of skeletal structures. These molecules are expressed both in early skeletal precursors and in the surface perichondrium and

Wilkins *et al.* [65] identified an SNP and a functional microsatellite associated with OA. It has been exhibited that various alleles of microsatellite are behind the modified transcriptional activity of BMP5 promoter suggestive of *cis*-regulation of

Chemokines are small, secreted proteins that stimulate the directional migration of leukocytes and mediate inflammation (Baggiolini et al, 1997). These are a family of heparin-binding cytokines known for this chemotactic activity. Four subfamilies of chemokines have been identified based on the juxtaposition of cysteine residues in the protein's N-terminus. These families have been named C,

periosteum layers that surround growing cartilage and bone [64].

**5. Chemokine (C-C motif ) ligand 2 (CCL2) gene**

*BMP5,* is involved in OA susceptibility.

C-C, C-X-C, and C-X3-C [66].
