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  • NMR was employed for the determination of un ligated


    NMR was employed for the determination of un-ligated domain 1 structure of DDR2 receptor. The collagen-binding site on the same was identified by cross saturation experiment and mutagenesis [40]. Birgit leitinger identified the binding site of collagen with DDR2 receptor, which was three spatially adjacent surface loops within the DS domain of DDR2, contains the collagen binding sites that involves in DDR2 signaling [41]. The DDR2 receptor recognizes the specific amino angiotensin 2 receptor blocker sequence of collagen. Initially, the recombinant triple helical variants of collagen type II were used for mapping the DDR2 binding sites that mapped the specific DDR2 binding sites to the second quarter of its collagenous domains [42]. The activation of DDR2 receptor displays the collagen specificity as it binds with collagen type II [41] and type X [42] favorably. GVMGFO (O = hydroxyproline) motif in the triple helix peptide of the ligand was identified to enable the crystal structure determination of the complex of DDR2 discoidin 1 domain [43]. This is a polar structure with GVMGFO motif being accommodated in an amphipathic binding pocket. During OA, the early cartilage damage causes the depletion of proteoglycan, lead to exposure of collagen type II protein, which further interact with chondrocytes via DDR2 [1,33]. Therefore, the cytoplasmic domain of DDR2 receptor is phosphorylated at tyrosine residue upon the binding of type II collagen, which commences the down-stream signaling pathway, inducing the expression of IL-6, IL-1βand MMP-13 mRNA in the deep layer of cartilage and resulting in cartilage destruction in joints of patients with osteoarthritis [44,45].Besides these, mechanical injury followed by the excess cartilage overloading may destroy the integrity of chondrocyte and osteophyte cells, in turn may cause osteoarthritis in patients without known earlier bone joint abnormalities. The cartilage degeneration and subsequent cell death of chondrocyte cells is occurred in response to mechanical injury due to release of reactive oxygen species. It is most interesting thing that mechanical injury mediated induction of OA disease progression has been initiated by the DDR2 expression and augmented activity as reported by the earlier reports [21,46,47].
    Role of DDR2 receptor in the development of Bone in human The significance of DDR2 receptor in the skeleton growth of human being could not be ignored, which has revealed by analysis of rare genetic disease, chondrodysplasia termed as spondylometa-epiphyseal dysplasia (SMED-SL) with short limbs and abnormal calcifications. This Autosomal disease has been characterized by presence of short stature, short limbs, broad fingers, bone abnormalities and premature calcifications. These autosomal diseases caused by the occurrence of three missense mutations in DDR2 and one spliced site mutation were identified in eight patients from seven different consanguineous families [48]. The mutation caused in DDR2 receptor leading to SMED-SL was analyzed by carrying out experiment in the human cell line to realize the cellular and biochemical mechanism. The three-missense mutation in DDR2 resulting in trafficking defect making the DDR2 protein retained in endoplasmic reticulum whereas forth mutation resulted in DDR2, which is perfectly trafficked to the cell surface but failed to interact with collagen due to mutation in the key residue of collagen binding sites [41]. Thus, the Autosomal disease SMED-SL is caused by at least two mutation leading to loss of function of DDR2 receptor that lack the ability to interact with collagen protein, resulting it in to severe skeleton abnormalities. This fact supports the essential contribution of DDR2 in human bone growth and developments. A current finding of DDR2 receptor contribution in the development of Murine Temporomandibular Joints (MTJ) has revealed by analyzing the primary culture of TMJ articular chondrocytes from wild type and DDR2slie/slie mice that showed abnormalities in chondrocytes maturity and mineralization in the absence of DDR2 [49]. This study also signifies the DDR2 is necessary for the normal development of TMJ condyle and maintain homeostasis of the extracellular matrix of joins. At the early stage of human developments, DDR2 receptor do contribute in bone growth and mineralization but mutation in this gene causes rare Autosomal diseases (SMED-SL) in a few cases where irregular mineralization is reported. It may be due to irregular/ lacks of regulatory mechanism involved in aberrant DDR2 expression and at late stage of life individual are prone to OA like condition. The mechanical stress, surgical damage etc. at joint tissue causes loss of extracellular matrix. The collagen that further binds DDR2 receptor in chondrocytes causes severe damage to cartilage by metalloproteinase’s but the intact pericellular matrix in turn protect DDR2 receptor being activated. Although DDR2 involve in bone development at early stage of life as per scientific report but due to changes in the pathophysiological condition of joints where DDR2 level gets incremented. Therefore, DDR2 seems to be dual mode of expression profile depending upon physiological condition and stages of life. It is also responsible for high expression at early stage of OA developments.