br Role of DDR receptor in the development of Bone

Role of DDR2 receptor in the development of Bone in human
DDR2 receptor and MMP-13 expression Type II collagen protein in articular cartilage is highly stable structure as its half-life is 117 years [43]. The chondrocytes have limited ability to synthesis type II collagen protein in the matrix of mature articular cartilage once the collagen gets disrupted. Collagenase-3 (MMP13) plays important role in the progression of OA as it has ability to cleave triple helix structure of collagen type II protein efficiently than that of MMP-1 [42]. Altered mechanical damage, aging, obesity etc. in OA are driving force toward degradation of pericellular matrix of chondrocytes. It enhances the exposure of chondrocytes towards type 2 collagen in matrix. The interaction of chondrocyte with Type 2 collagen results in upregulated ion channel of DDR2 receptor and MMP-13, subsequently degradation of type II collagen and aggrecan occur [42,50]. Deposited fragments of aggrecan and type II collagen may further increase the synthesis of MMP-13 upon integration with DDR2 receptor [30] or through binding to another receptor [51]. DDR2 receptor in chondrocytes may enhance its activation with TGF-β being up-regulated in destructed ECM. In turn it may acts as positive feedback loop for expression of MMP-13 causing severe damage to cartilage through IL-1β and TNF-α induction. In report mention on heterozygote DDR2 null mice revealed the partial protection against the experimental OA mice model and also facilitated evidence of diminished MMP13 expression level [6], fortifying that DDR2-MMP13 loop involve in onset of OA. The attenuation of DDR2 receptor activation in chondrocytes by the antagonist may block the both loop of DDR2 activation via TGF-β and type II collagen, leading to downregulation of MMP13 through IL-1β and TNF-α. Therefore, we may conclude that blockage of DDR2 receptor through ligand antagonism could play a protective role in chondrocytes formation through inhibiting the destruction of cartilage by MMP-13 by suppressing the TNF- α, IL-1β.
Signaling of DDR2 receptor and its regulation Being the tyrosine kinase receptor, downstream signaling of DDR2 receptor is initiated by phosphorylation of cytoplasmic tyrosine residue upon ligand binding (Type II collagen) but the authentic facts or detail information of tyrosine phosphorylation upon the binding of collagen protein is not still clear to the researcher. A recent study on the phosphoproteomic showed that the collagen provoked DDR2 auto-phosphorylation were identified at two sites of the kinase domain (tyr684and tyr813) in the DDR2 signaling pathway [59]. Additionally, an intriguing fact came in light about the site of JM domains (tyr481) that was found to be phosphorylated constitutively [60] but phosphorylation of tyr471, which was reported to be the docking site for adaptor shcA. Further Tyr471was not recognized utilizing anti-phosphotyrosine immune-precipitation and peptide identification following the protein digestion [60]. The expression of DDR2 receptor in various systems is different and implicates the involvements with several transcription factor/complexes. The ATF4-C/Ebb transcription factor is responsible for DDR2 expression in osteogenic differentiation system [24]. In case of rat VSM cells, hypoxia or hyperbaric oxygen responsible for the enhanced My-Max binding activity of DDR2 promoter region lead to the increased expression of DDR2 receptor [54]. However, the signaling and regulatory mechanism of DDR2 receptor is quite different depending upon the site of expression and types of molecules being sensed. In case of osteoarthritis, cartilage produces type II collagen in major amount which binds to DDR2 receptor provoking the activation of metalloproteinases (MMPs) for degradation of cartilage and DDR2 itself being activated in this cascade. Therefore, either inactivation or proper antagonist binding into DDR2 active site in OA induced mice model may stop the extent of disintegration of cartilage and the severity of diseases.