Osteoarthritis (OA) is a degenerative process in joints characterized by functional deterioration, abrasion of articular cartilage and formation of new bone at and around joint surfaces. The disease is estimated to affect approximately 16 million adults in the United States. It has become a disease of major concern to the medical community due to the increasing longevity of the population. Current therapies are primarily palliative. There is a particular need to elucidate molecular mechanisms that lead to cartilage destruction such that methods for halting or even reversing the progression of the disease can be developed. The hallmark of early OA is cartilage matrix degradation. Collagenases are members of the matrix metalloproteinase (MMP) family which play a major role in this cartilage destruction. The investigators hypothesize that collagenases play an important role in cartilage remodeling during growth and development, and in the degradation of cartilage matrix in OA. They further hypothesize that MT1-MMP plays a critical role in the degradation of cartilage matrix and may be responsible for a shift in chondrocyte metabolism to a state of accelerated catabolism. To test this hypothesis, they propose to analyze the in situ spatial and temporal expression of the collagenases, MMP-1 and -13, in guinea pig knee joints. They will focus on mechanisms of collagen matrix degradation through an analysis of the interaction of the collagenases and the gelatinases, MMP-1 and MMP-9, and the cartilage-expressed MT1-MMP, activator of MMP-2 and MMP-13. Gene and protein expression for these MMPs at different stages in the guinea pig model of OA will be correlated with quantitative measures of collagen degradation, including quantitative polarized light microscopy, urinary and plasma pyridinoline and deoxypyridinoline cross-links, and synovial fluid MMP activity. The unique aspects of this guinea pig model include the spontaneous development of characteristic OA lesions, the similarity of these lesions to those of primary knee OA of humans, and the slowing of OA disease progression in the knee with weight reduction, as in humans. The investigators plan also to evaluate three other guinea pig strains for their suitability to serve as age-matched, OA-resistant controls. The applicants suggest that the guinea pig model of knee OA is an outstanding system in which to characterize the molecular events of OA. They propose that successful completion of this work will serve as a basis for future studies of drug intervention for OA, and characterization and interaction of other pathogenic molecules in OA.
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