**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 traits [52].

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 skeletal tissue [58].

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

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 *BMP5,* is involved in OA susceptibility.
