br The contribution of Interference RNA
The contribution of Interference RNA and epigenetic in OA attenuation Interference RNA, a cellular mechanism for post-transcriptional gene silencing that is associated with mRNA. The potential of RNAi has successfully silenced the wide range of protein coding genes. Its high specificity sanctions the attenuation of diseases cognate alleles. Gene silencing performed by RNAi against DDR2 receptor demonstrated the reduction in AI-10-49 synthesis level of IL-6 in chondrocytes, which inferred the DDR2 receptor contribute the significant role in collagen mediated release of IL-6 . Recent studies corroborated the regulation of gene expression at post-transcription level through microRNA mediated RNA interference is the novel mechanism. The expression of microRNA profile in human OA chondrocytes has demonstrated to be correlated with expression of MMP-13 with specific microRNA [, , ]. In the previous studies it has been established that DDR2 mediated MMP-13 expression in chondrocytes in OA is carried out. Another study showed the overexpression of mir-27b suppresses the activity of reporter construct with 3\'-UTR of human MMP-13 mRNA leading to the inhibition of IL-1β mediated MMP-13 expression in chondrocytes . Collagen II mediated DDR2 activation can show the variable behavior depending upon the cell type. siRNA mediated DDR2 silencing in lung micro fibroblast cell showed prominent reduction in the DDR2 expression followed by the blockage of ECM fragments accumulation such as fibronectin and collagen .Therefore, information derived from the work done on the role of RNAi, epigenetic factor, siRNA etc. have strongly suggested that inhibition or suppression of DDR2 activation in chondrocytes or fibroblast cultures in vitro diminishes the expression level of MMP-13, IL-1β and IL-6 mediated MMP-13. This transpired due to blockage of phosphorylation and the expression of DDR2, which completely check the down regulatory signaling pathway pertaining to degradation of cartilage tissues. Advantage associated with therapeutic application of RNAi, siRNA against DDR2 receptor in cartilage may provide efficacy and specificity of the treatment and reducing the toxicity simultaneously. A few researches in the context of DDR2 silencing using RNAi therapy has been carried out to establish the role of DDR2 in improvement in OA cartilage. However, work on siRNA mediated DDR2 silencing in lung micro fibroblast cell showed prominent reduction in the DDR2 expression followed by the blockage of ECM fragments accumulation such as fibronectin and collagen , which fortify the potential role in blocking the damage of ECM. In order to strengthen the RNAi role in suppression of DDR2 expression, much more investigative research in human OA cartilage need to be executed to verify the robustness of RNAi technology in OA treatments. Therefore, DDR2 receptor targeting via interference RNA technology or pharmacological development of diseases modifying drugs could be the prospective treatment option. It may bring possible remedy against Osteoarthritis.
DDR2 receptor antagonism and osteoarthritis DDR2 is a special kind of receptor that distinguished from other RTKs by discoid (DS) domain structurally of 162 amino-acid long motif in extracellular part. The reduction in the level ofDDR2 expression in mouse model is concerned with the delayed progression of condylar cartilage degeneration, induced with either type XI collagen or partially discectomy . Actinomycin D, an antibiotic has been used clinically for the treatment of cancer. A new biological function of Actinomycin D has been reported to be intervened the activation of DDR2expression in the insect cell-based method . Other small DDR antagonists have also been reported but it is not concrete to DDR2. Moreover, increased expression of the collagen receptor discoid in domain receptor 2 in articular cartilage has a prime important and regulatory event in the pathogenesis of osteoarthritis [4,6,29]. Therefore, DDR2 antagonist could be the new insight into the drug discovery and development of diseases modifying drug against the osteoarthritis in the upcoming future. DDR2 expression may be the primary stage cascade for the initiation of OA disease. Consequently, designing, development of suitable and concrete DDR2 antagonist molecule could be the impressive therapeutic approach towards the curing of OA in near future. If some lead macro or micro molecules would be designed specifically against DDR2 as antagonist, then they could prevent the collagen 2 proximity and subsequent binding towards DDR2 for initiating the OA diseases explained in in the Fig. 4.