The long-term goal of this study is to understand the pathogenesis of osteoarthritis (OA)-like changes in articular cartilage that are associated with osteochondrodysplasias caused by mutations in extracellular matrix proteins. This grant application is based on findings that (1) type IX collagen-deficient (Col9a1-/-) or type XI collagen haploinsufficient mice (heterozygous chondrodysplasia, cho/+) mice develop progressive OA-like changes in knee and temporomandibular (TM) joints;(2) the levels of expression and activity of matrix metalloproteinase 13 (MMP-13, collagenase 3), a major cartilage collagen-degrading proteinase, are increased in the articular cartilage of knee joints in both mutant mice;(3) the expression of a collagen receptor, the discoidin domain receptor tyrosine kinase 2 (Ddr2), is also increased in the articular cartilage of knee joints in both mutant mice;(4) the expression and activity of MMP-13 and the expression of DDR2 are increased in a surgically induced mouse OA model and in human hip OA cartilages;(5) increased MMP-13 expression in chondrocytes results from type II collagen-induced activation of DDR2 in vitro;(6) the Ras/Raf/MEK/ERK pathway is involved in the DDR2-dependent up-regulation of MMP-13 expression in human chondrocytes. These findings form the basis of the hypothesis that cartilage collagen mutations lead to degenerative changes in articular cartilage in a process characterized by two phases. In an early phase. alterations in chondrocyte metabolism result in proteoglycan degradation and changes in the composition of the pericellular matrix including more collagen II fibrils in the vicinity of the cells. In a late phase, enhanced interactions between type II collagen fibrils and resident chondrocytes lead to activation of DDR2, increased expression of DDR2 and MMP-13, and a progressive and irreversible destruction of the collagen network. To test the late phase aspect of our hypothesis, we propose the following Specific Aims: 1) To investigate the role of increased Ddr2 expression as a factor leading to early-onset OA-like pathology;2) to investigate whether inhibition of DDR2 signaling will delay the onset of OA in Col9a1-/- and cho/+ mice;and 3) to investigate the mechanism by which DDR2 induces the expression of MMP-13 in human chondrocytes. This study should not only provide novel insights into the role of DDR2 in the progression of genetic forms of OA, but may shed light on aspects of disease progression in non-genetic forms as well.
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