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

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

Sozzani *et al.* [67] said that the C-C and C-X-C chemokines represent two significant subgroups. The C-X-C chemokines include IL-8 and growth-related oncogene a. The C-C chemokine family comprises families of monocyte chemoattractant proteins (e.g. MCP-1, MCP-2, MCP-3), macrophage inflammatory proteins (e.g., MIP-1a and MIP-1b), and a chemokine designated RANTES (regulated upon activation, normal T cell expressed and secreted). As their names suggest, these chemokines act predominantly on mononuclear cells (e.g., T cells, monocytes, and macrophages).

CCL2; previously known as monocyte chemoattractant protein-1, MCP-1 is a chemoattractant that belongs to the CC chemokine subfamily. Mehrabian *et al*. [68] localized the gene for monocyte chemotactic protein-1 (CCL2) to chromosome 17. Corrigall *et al*. 2001 proposed that CCL2 in the synovial membrane serves to recruit macrophages and perpetuate inflammation in the joints of patients with rheumatoid arthritis. CCL2 plays a crucial role in host defense by recruiting monocytes and macrophages at the site of inflammation [69].

CCL2 production is inducible in various types of cells, including synoviocytes [70]. In several studies, increased expression of CCL2 was observed in patients with inflammatory diseases, including neuropsychiatric syndromes of systemic lupus erythematosus, rheumatoid arthritis, OA and degenerative and inflammatory arthropathies, including gout [71–73].

Reports have demonstrated the involvement of chemokines in cartilage abnormalities in OA [74–76]. Reported studies suggests that CCL2 is involved in inflammatory diseases such as RA and OA, However, in previous studies, the CCL2 gene polymorphism (22510A/G) did not show any association with Spanish and Korean RA [77, 78]. However, Park *et al*. [79] investigate that significant association between polymorphisms of the CCL2 gene and primary knee OA patients in a Korean population.
