Degenerative joint disease or osteoarthritis (OA) is one of the most common disabling diseases affecting middle-aged and older people. It is characterized by the breakdown of unstable matrix network in cartilage. To better understand the pathogenic process of OA, it is necessary to examine how the matrix structure is assembled in mature cartilage, and what causes degeneration of such a structure. The long-term objective of this study is to analyze the molecular mechanisms of stabilizing matrix structures in cartilage. In particular, the role of matrilins (MATN) in stabilizing extracellular matrix network in cartilage will be examined. Matrilins are novel adhesive oligomeric extracellular matrix molecules whose defect causes multiple epiphyseal dysplasia manifesting with early-onset osteoarthritis. The hypothesis is based on our following findings. First, matrilins form a filamentous network to maintain matrix adhesions. This assembly process is well understood for MATN1, but not for MATN2 that contains a unique domain. Second, such filamentous network can be destabilized by proteolysis of matrilins. The identity of the matrix protease that cleaves matrilins is unknown. Third, chondrodysplasia-associated MATN3 mutant fails to form a filamentous network. Therefore, assembly defect and/or excessive proteolysis of matrilins may cause an unstable cartilage matrix network. To test this hypothesis systematically, we will analyze the assembly process of MATN2 (Specific Aim 1), identify the matrix protease that cleaves matrilins (Specific Aim 2), analyze in vitro the mechanism for the failure of MATN3 mutant to form filamentous network (Specific Aim 3), and characterize in vivo the consequences of disrupting matrilin filament formation on cartilage matrix structure (Specific Aim 4). These data will contribute not only to our basic understanding of cartilage matrix assembly, but also to the development of methods for prevention and treatment of cartilage degeneration. ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Kohanski, Ronald A
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Rhode Island Hospital
United States
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