In osteoarthritis, the major and central changes occur in the hyaline cartilage. Remodeling and repair of the joint structure often accompany the progression of disease and the ability of cartilage to repair has been questioned. To provide a basis for comparison to the pathological situation, it is necessary to define the basic mechanisms that regulate expression of a specific extracellular matrix. It is proposed that cartilage chondrocytes respond to environmental factors by synthesizing specific products which may or may not contribute to maintenance of proper matrix architecture and function. This will be investigated by continued studies defining the influence of specific factors such as IGF-I and TGF-B (positive modulators of type II collagen synthesis) and IL-1 and gamma interferon (negative modulators) on biosynthesis of the predominant classes of cartilage matrix molecules (collagen, proteoglycans and link proteins) and the mechanisms through which they act. Specific questions asked will be: is the matrix phenotype coordinately regulated? How do factors potentially in the environment of the chondrocyte such as cytokines and immune mediators affect the expression of the appropriate phenotype? and what factors are necessary to promote synthesis of the proper phenotype? A model system has been developed and characterized in which bovine articular chondrocytes in high density monolayer culture can be used to determine the biosynthetic capability of the cells. The methodologies of molecular biology and biochemistry will be used to investigate gene expression in adult articular chondrocytes. Large aggregating proteoglycans, small proteoglycan, type II collagen and link proteins will be measured. Eventually, the response of adult tissue will be compared to that of fetal and calf cartilage. In addition, detailed analyses will be undertaken on the mechanism of regulation of type II collagen gene transcription and biosynthesis of multiple link proteins. These findings may be extremely significant to the concept of cartilage as an anlage to bone, in """"""""aging"""""""" joint cartilage and in diseases or injured cartilage.
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