PROTEOGLYCAN METABOLISM IN OSTEOARTHRITIS

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Osteoarthritis is a slowly progressive destructive disease of the joints which is widespread in man and other animal species. The underlying cause(s) of osteoarthritis have not been identified despite numerous histological, biochemical and biomechanical studies examining the changes that occur as the disease develops. In humans, osteoarthritis takes years to develop and at present the disease cannot be diagnosed until quite late in the degenerative process. Thus current medical treatment consists of mainly trying to reverse the later, inflammatory stage of the disease. At present there is a particular need for methods detecting the early stages of osteoarthritis so that factors lead to the cartilage destruction can be better understood. In this proposal we describe preliminary data identify- ing, in osteoarthritic cartilage proteoglycans, the occurrence of struc- tural "markers" that are indicative of the initial biochemical changes leading to the onset of osteoarthritis. These markers consist of atypical structures in the chondroitin sulfate (CS) glycosaminoglycans of osteoarth- ritic proteoglycans. The objectives of this proposal are to further investigate this novel finding. The specific aims to achieve this objec- tive will be: 1. To determine the relative occurrence of atypical CS structures in proteoglycans from normal and osteoarthritic human cartilage using monoclonal antibodies that specifically recognize these structures. 2. To perform similar studies in two animal models that mimic the onset of osteoarthritis in man, i.e., the development of spontaneous OA. 3. To further characterize the specificity of monoclonal antibodies that recog- nize atypical CS structures and develop immunoassay procedures to measure the expression of these atypical CS structures in cartilage, serum and/or synovial fluid. 4. To perform in vitro cell culture studies to inves- tigate the biosynthesis of proteoglycans containing these atypical struc- tures, and to see cytokines and growth factors modulate the expression of these structures. 5. To perform immunohistochemical studies on normal and osteoarthritic cartilage to establish if focal or general expression of the epitopes occur in OA. Overall, the studies outlined in this proposal should lead to a better understanding of factors involved in the onset of osteoarthritis and may lead to the development of means for halting or reversing the disease process.