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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014399-08
Application #
6836506
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Kohanski, Ronald A
Project Start
1997-04-15
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
8
Fiscal Year
2005
Total Cost
$346,500
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
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