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  • Thonzonium Bromide br How does DDR receptor activated to


    How does DDR2 receptor activated to induce Osteoarthritis Alternation of joints by mechanical stress produces microcracks and deterioration of natural pores in subchondral bone provides Thonzonium Bromide for cross talk through diffusion of small molecules [26,27]. At early stage of OA, chondrocytes in the injured cartilage releases transforming growth factor beta (TGF-β) via SMAD 2/3 signaling network, which contributes in maintenance of quiescent phase of chondrocytes, aggrecan and collagen II. Yes, it is true that TGF- β is released from the damaged cartilage in the initial stage of OA. The chondrocytes in cartilage are the responsible for maintaining the integrity of tissue. The chondrocytes respond the damaged collagen network at injury site by incrementing the level of transforming growth factor-β (TGF- β), integrin and collagen synthesis. It may facilitate the attempt of being repaired towards the damaged cartilage. If it fails to repairs the tissue, damaged components such as collagen type II may integrate with DDR2 receptor in chondrocytes to activate it by binding of collagen 2 with the DDR2 active site and could secrete MMP-13, leading to severe cartilage damage (OA)in response to TGF-β and collagen networking signaling pathway in negative mode of role.In addition to protective role of smad 2/3 signaling, it may also promote TGF-β formation of chondrophytes and osteophytes [28]. Formation of osteophytes at the margin of cartilage is characteristic properties of OA. Collagen II ligand binding in DDR2 provokes the receptor activation that further induces negative impacts on ECM and chondrocytes. The up-regulation of DDR2 expression level in presence of collagen II on chondrocytes is the keys event in pathogenesis of OA as reported earlier [29]. Further studies again fortify that collagen II may exacerbate OA by enhancing the induction and increasing the level of MMP-13 following the aberrant activation and binding with DDR2, which degrade the collagen matrix and making a step for the positive feedback loop [30,31,32]. Early depletion of cartilage in OA causes the degradation of proteoglycan led to exposure of collagen II, which may further interact with chondrocytes upon binding to DDR2 [33]. Thus, the extrinsic activation of DDR2 upon integration with collagen II may induce the overexpression of hypertrophic markers such as MMP-13 following the upregulation of TNF-α [30] and thus TGF-β acts an initiator of OA in the subchondral bone joints [34]. TGF-β1, may eventually lead to activation of DDR2 and consider their importance in the development of OA. Earlier sign in articular degeneration is high production of proteoglycan in mouse model of OA [35]. Over expression of TGF- β1level in human osteoarthritis tissue is also outlined when compared to healthy articular cartilage [36], which also supports the involvement of TGF-β1 in early onset of OA. Those condensed progenitor cells inside the osteophytes are supposed to differentiates in to chondrocytes, which undergoes chondrogenesis to produces collagen II and Aggrecans. TGF-β induced serine proteases (HTRA1) disrupts the pericellular matrix may be one of the earliest events occur in the activation of chondrocyte cell surface receptor [37]. Therefore, TGF-β may indirectly involve in activation of DDR2 receptor in chondrocytes as it allows the aggregation of collagen II in pericellular matrix. At early stage of cartilage damage, the depletion of proteoglycans occurs resulting in exposure of collagen II with chondrocytes. During the entire life of individual, articular chondrocyte as well as subchondral bone receives acute or chronic stress. Joints homeostasis is maintained by biomechanical stress, as rapid loss of proteoglycan in joints occurs due to immobilization or disuse. These osteophytes are fibrocartilage capped with bony out growth at margin of joints. The experiment on Murine OA model clarified that the osteophytes derived from MSC-periosteal lining cells at junction of bone-cartilage but not at synovial lining [38,39].