Our long-term objective is to document changes associated with the early stage of osteoarthritis (OA) in dogs and to identify factors that modify the disease. This proposal has two main and related objectives: 1) to identify the role of fibronectin in cartilage, and 2) to identify factors biochemical or mechanical, which influence fibronectin biosynthesis in cartilage and promote increased production of this biding protein by chondrocytes in the degenerative cartilage of individuals with incipient or obvious OA.
Our specific aims are: 1) To characterize a recently identified matrix proteoglycan which binds tightly to fibronectin in cartilage, and to define at the molecular level, those structural characteristics of cartilage fibronectin which make it distinct from plasma or synovial fluid fibronectin. This information would permit us to clarify the mechanisms by which fibronectin binding is involved in matrix organizational and function. 2) To establish that chondrocytes in OA cartilage in vivo differ from normal cells because they synthesize increased amounts of fibronectin. We would use available cDNA as a probe for increased mRNA for fibronectin and also use new methods of flow cytometry to characterize chondrocytes shape, increased mitotic activity, and receptors for fibronectin. This would constitute strong evidence that increased synthesis by the chondrocyte is a major factor in fibronectin accumulation in OA cartilage. 3) To culture cartilage for up to two weeks in a defined media, supplemented with insulin and calcium sufficient to maintain optimal levels of proteoglycan synthesis; to determine rates of collagen and fibronectin synthesis under these conditions and to use addition of factors such as TGF-B, interleukin-1 or the application of precisely defined cyclic and static compressive forces on cartilage explants in defined media to induce increased fibronectin accumulation in conjunction with proteoglycan loss. this would permit us to mimic, in vitro, two well known characteristics of degenerating cartilage in OA joints. The proposed experiments are designed to test the hypothesis that fibronectin has a purposeful role in cartilage homeostasis and that increased levels of fibronectin in the degenerative cartilage reflect a perturbation in chondrocyte function and result in disruption of matrix assembly and cartilage destruction in OA.
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