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
Yang, Xu; Trehan, Samir K; Guan, Yingjie et al. (2014) Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist. J Biol Chem 289:34768-79
Wei, Fangyuan; Moore, Douglas C; Wei, Lei et al. (2012) Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway. Arthritis Res Ther 14:R177
Jayasuriya, Chathuraka T; Goldring, Mary B; Terek, Richard et al. (2012) Matrilin-3 induction of IL-1 receptor antagonist is required for up-regulating collagen II and aggrecan and down-regulating ADAMTS-5 gene expression. Arthritis Res Ther 14:R197
Li, Jing; Huang, Jingang; Dai, Liming et al. (2012) miR-146a, an IL-1? responsive miRNA, induces vascular endothelial growth factor and chondrocyte apoptosis by targeting Smad4. Arthritis Res Ther 14:R75
Guan, Yingjie; Chen, Qian; Yang, Xu et al. (2012) Subcellular relocation of histone deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV. Am J Physiol Cell Physiol 303:C33-40
Guan, Ying-Jie; Yang, Xu; Wei, Lei et al. (2011) MiR-365: a mechanosensitive microRNA stimulates chondrocyte differentiation through targeting histone deacetylase 4. FASEB J 25:4457-66
Wei, Lei; Kanbe, Katsuaki; Lee, Mark et al. (2010) Stimulation of chondrocyte hypertrophy by chemokine stromal cell-derived factor 1 in the chondro-osseous junction during endochondral bone formation. Dev Biol 341:236-45
Chang, Jen-Huei; Shen, Hsain-Chung; Huang, Guo-Shu et al. (2009) A biomechanical comparison of all-inside meniscus repair techniques. J Surg Res 155:82-8
Sun, Xiaojuan; Wei, Lei; Chen, Qian et al. (2009) HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity. J Biol Chem 284:21881-90
Phornphutkul, Chanika; Lee, Mark; Voigt, Cliff et al. (2009) The effect of rapamycin on bone growth in rabbits. J Orthop Res 27:1157-61

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