• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • br DDR receptor and MMP expression


    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 expression 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. Matrix metalloproteinase (MMP), an Science Daily and indicator molecule in pathological state that provides cartilage health under both physiological circumstances and osteoarthritic state, which have already been studied earlier [52]. Collagen type II molecules is released upon joint injury that could act on DDR2 receptor through RAS/RAF/MEK/ERK and p38 signaling pathways that further activate MMP-13 to damage extracellular matrix [4,6]. Some studies have also been provided evidence that collagen-2 involves in expression of IL-1, IL-6, IL-8, IL-1β as well as MMP-1, 2, 13 via mitogen activated protein kinase p38 (MAPKp38) and Nuclear factor kappa B (NF-kβ) signaling pathway [53]. Based on the above findings, it may be concluded that RAS/RAF/MEK/ERK and p38 could be the intermediate molecules through which MMP-13 expression may be incremented upon the binding of collagen type II to DDR2 receptor in chondrocytes. This may provide important clue where MMP breakdown the extracellular cartilage matrix exposing chondrocytes to collagen type II, which induces the extra release of degradative enzyme, causing further degradation of cartilage. Since, the MMP-13 expression in human cartilage with osteoarthritis has been previously reported to be upregulated compared to that of normal [43,52,54,55]. A similar observation has also been reported in knee joint cartilage of mouse model showing the osteoarthritis like changes due to constitutive expression of MMP-13 [56]. In support of this, a recent study in mice deleted with MMP-13 enzyme demonstrated delay the progression of articular tissue [23]. However, the up regulation of DDR2 receptor implicates MMP-13 induction in chondrocyte [29,57]. The earlier report indicates that MMP-13 is major effectors in mechanically induced joint destruction in case of osteoarthritis. However, MMP-13 may be over expressed followed by their up regulation in case of other type of arthritis such as rheumatoid arthritis, but there is no chance of possible involvement of DDR2 activatedIL-1β, IL-6 upregulation followed by the MMP-13 hyperexpression. However, few reports suggest the involvement of DDR2 receptor in fibroblast cells in rheumatoid arthritis but that is not sufficient evidences to establish the direct connection of DDR2 and way of its activation along with MMP13 expression are key regulator for initiation of RA disease progression. Moreover, RA is basically an autoimmune disorder where, pro-inflammatory cytokines like IL-1β & TNF-α are upregulated at initial stage followed by the activation of joint matrix metallo proteinase expression. Moreover, the activation of the DDR2 happens only in the downstream cascade of disease progressive signaling pathway at later-stage. So, therapy with DDR2 antagonist might not be fruitful in case of RA. Conversely, the important biomarker associated with degradation of articular cartilage at early phase of OA may comprises collagen ligand mediated DDR2 activation followed by a number of matrix-digesting enzymes such as metalloproteinase family, the disintegrin and metalloproteinases with thrombospondin type 1 motif (ADAMTS) family, MMP-9, MMP-13, Aggrecanase etc. [58]. Out of which, attention may be focused on MMP-13 as it is significantly over-expressed in osteo-arthritic joints and cartilage in the later stage following DDR2 receptor activation, which is hardly recognized in normal cartilage and RA disease initiation.