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  • br Prospect of DDR antagonist DDR a receptor

    2019-08-21


    Prospect of DDR2 antagonist DDR2, a receptor of tyrosine kinase has been found now to be reported to play a significant role in onset of osteoarthritis at the early stage of diseases progression. The DDR2 are the receptor for extracellular collagen and activated upon the binding of collagen resulting in complex signaling networks expounded by above mentioned findings. An in-silico molecular docking study of various natural and synthetic molecules against the DDR2 receptor is one of the ways to design and develop the DDR2 antagonist as anti-OA drug through lead optimization followed by the assaying of those compounds through the receptor marker in chondrocyte and osteophyte cell culture and in vivo assay to validate its efficacy. We are endeavoring to develop potent and selective inhibitor against DDR2, which further could be implicated pharmacologically to demonstrate the inhibitory impact on kinase activity of DDR2. Others have reported some DDR2 inhibitors [68] but the validation neither of these compounds at cellular model level nor the degree of selectivity for DDR2 has explored. The inhibition of DDR2 receptor spectinomycin with the antagonist in the patients with osteoarthritis could completely block the down streaming signaling network, provoking the chondrocytes not to release MMP-13, IL-6, TNF-α etc. in ECM and may check the cartilage degradation initiated by the OA [69]. However anti- MMP-13, IL-6 and TNF-α agents could manage the OA at the last stage of disease pathway, but they could not heal the OA specifically, as MMP-13, IL-6 and TNF-α up-regulation may occur in several inflammatory disorders including rheumatoid arthritis, psoriasis and other auto-immune disorders. Designing of selective DDR2 antagonist which may strongly bind with the active site of tyrosine kinase receptor of DDR2 may inhibit the adhesion of collagen 2 ligand with spectinomycin the receptor in the osteophytes cell surface. This phenomenon may lead to arrest the further progression of OA disease markedly and ameliorate the disease successfully.
    Discussion Osteoarthritis, one of the disease conditions for which treatment available is symptomatic relieve from pains but unable to control the diseases progression and permanent cure. Since, osteoarthritis progression cannot be halted if we don’t prevent the early events of onset of O.A and specific triggering factors responsible for disease initiation. With above-mentioned review of the studies suggest that DDR2 receptor could be the promising drug target [69] against the osteoarthritis for noteworthy therapeutic management. The increment of expression level of MMP-13, a key regulator of matrix destruction associated with the early pathogenesis of OA is up regulated byDDR2 receptor activation in chondrocytes in mouse model and human patients’ sample [24]. The over-expression of DDR2 in many models of OA is one of the key factors responsible for early stage of osteoarthritis progression because of the decrease in the expression of DDR2 receptor in chondrocytes of mouse model attenuates the cartilage degeneration [24].
    Conclusion The involvement of DDR2 receptor activation in pathogenesis of osteoarthritis seems to be active players as it contributes in severe destruction of cartilage via metalloproteinase expression. The information presented in this review illustrates that the DDR2 activation may involve in the osteoarthritis at the early stage. Identification of molecules as antagonist to DDR2 receptor could be the promising therapeutic targets against the osteoarthritis through lead optimization. It may intervene the down regulatory pathway, in which metalloproteinases are involved in being activated. As downstream signaling mediators such as MMP expression, IL-6, IL-12, IL-1β and TNF-α up-regulation are the common features of all auto-immune disorders including rheumatic arthritis, celiac disease, diabetes mellitus type 1, Graves\' disease, inflammatory bowel disease, multiple sclerosis, psoriasis etc. But DDR2expression is not actively related with those auto-immune disorders significantly at preliminary stages. However, DDR2agonistic action mediated MMP expression, IL-6, IL-12, IL-1β, TNF-α up-regulation through TGF-β and collagen signaling are solely related with the onset progression of OA disease. Therefore, designing of DDR2 receptor antagonist for blocking the collagen type 2 ligand protein binding through TGF-β signaling rather than the developing inhibitor of MMP-13, MMP-1, MMP-9, IL-6, IL-12, IL-1β and TNF-α could be the rational, effective, specific and safe drug discovery approach towards the OA treatment and possible cure. Research in the epigenetic and RNAi analysis against DDR2 in OA is at plinth but the available information may suggest the various mechanisms involve in pathophysiology of OA. Pharmacological inhibitors against the DDR2 receptor need to be identified through in-silico modeling and subsequent preclinical and clinical studies for the OA patients, which could have highest therapeutic value with lowest side effects for anti-osteoarthritis blockbuster drug development. Although still extensive research in respect to DDR2 association in osteoarthritis needs to be undertaken in order to reach in the successful development of treatment regimen for the permanent cure of this devastating disease. Apart from in-vitro screening of DDR2 antagonist molecule, in-vivo experiment should be carried out in near future to develop an established and potential disease modifying anti-osteoarthritis drug molecule. In order to establish such model, the expression level of DDR2 from fibroblast cells in chondrocytes should be determined in the mechanical injury/oxalo-acetate induced osteoarthritis mice model. The DDR2 expression level of must be measured and compared with the uninjured/oxalo-acetate un-treated mice to validate the functional role of DDR2 in the osteoarthritis initiation. This experimental model could play a major role for successful in-vivo screening of the anti-osteoarthritis drug through DDR2 signaling in near future.