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  • BMI1 inhibitor Since anti MMP Therapy anti


    Since, anti-MMP Therapy [9], anti-iNOS therapy [10], TNF-α and IL-1β inhibitor (Diacerhein) [11] etc. are some of the disease modifying anti-osteoarthritis drugs have been used. But their action based on the evidence from the clinical trial and scientific literature suggesting the therapeutic efficacy in OA is fragile. Moreover, the current drugs including diseases modifying anti-arthritic drugs used for the treatment of OA provide only symptomatic relief to patients from pains and inflammation, but this pharmacological intervention does not attenuate the articular cartilage degeneration mediated OA disease syndrome. Therefore, there is a priority to switch the effective target to DDR2, which could suspend OA specific multi-direction signaling pathway to circumvent the degradation of cartilage.
    Genomic location, classification and regulation of DDR2 The gene encoding DDR2, also known as CD167b is located on the chromosome number 1 (1q23.3) and composed of 19 BMI1 inhibitor part, out of which 4-19 are coding exon [12]. In the early 90 s, several researchers have identified the protein with unusual N-terminal discoidin-I like domain and C-terminal kinases domain by the cloning of a novel class of transcripts and determined domain with 45% identical to Neurotrophin receptor, TrkA. Later on, these transcripts were given a unique name such as DDR, Trk E, NEP, CAK, RTK-6, PTK-3, MCK-10, CCK-2, TKT andTyro-10. Furthermore, these proteins have been reported to have unusual receptor tyrosine kinase (RTK)structure [12,[13], [14], [15], [16], [17], [18], [19], [20]]. DDR, Trk E, NEP, CAK, RTK-6, PTK-3, and MCK-10 are further classified and renamed as DDR1 while Tyro-10, CCK2 and TKT as DDR2 receptor based on the N-terminal homology [1,2]. DDR1 and DDR2 lies between the intersection of big receptor family. DDR family members (Fig. 1) are generally expressed in inflammation, fibrosis, cancer etc., out of which DDR2 only regulate the osteoarthritis disease progression. In cancer, both DDR1 and DDR2 are expressed. In inflammatory osteoarthritis status are initiated by the aberrant activation of DDR with extracellular matrix collagen 2 as ligand in response to cartilage degeneration due to mechanical injury and ageing process in adult. Since, DDR2 is specifically expressed in joint cartilage and chondrocytes isolated from temporomandibular joint of DDR1-null mice by the collagen 2 ligand binding [21]. In order to activate DDR2 in erratic way, collagen BMI1 inhibitor 2 is released from the joint cartilage which further confirms the OA disease progression followed by the MMP-13 hyper expression [1]. The site of DDR1 expression is epithelial cells and immune cells including mononuclear cells whereas for DDR2 expression, in the mesenchymal cells including osteophytes and chondrocytes. However, DDR2 was also reported to express in Neutrophils [1,22]. In case of normal cells, both DDR1 and DDR2 are not expressed whereas DDR1 but not DDR2 seems to get expressed in well differentiated epithelial cancer cells only. During the OA, both aggrecan and collagen are degenerated by enzyme Metalloproteinase belonging to ADAMTS and Metalloproteinase released from chondrocytes [23] [22]. This cascade has been related to site where DDR2 is expressed may show strong evidence link to the human disease osteoarthritis displaying age-dependent cartilage degeneration and mechanical injury. The expression of DDR2 receptor has regulated by numerous types of factors depending upon the cell type. During the osteogenic differentiation, the transcription factorATF4 combined with CCAAT/enhancer binding site in the DDR2 promoter, which is responsible for induction of DDR2 transcription [24]. In case of hepatic cells, liver injury has been reported to be acted as a factor for the up-regulation of DDR2 mRNA expression [25]. As above said DDR2, a microenvironment sensor is tyrosine kinase receptor, which can be regulated by various factors depending upon the cell type, in which DDR2 is being expressed.