The properties of articular cartilage necessary for effective weight- bearing depend directly upon the composition and complex structural organization of the matrix, which in turn result from the metabolism of the sparse cell population. Articular chondrocytes are metabolically heterogeneous in intact cartilage, and in cell culture after isolation from the tissue, they continue to express differences in their metabolism of proteoglycans, collagens, and other proteins, and they vary in their responses to growth factors the cytokines. Furthermore, it is well recognized that the most superficial region of the cartilage frequently shows the earliest osteoarthritic changes. The long-term objectives of this project are to understand the importance of chondrocytic heterogeneity in the maintenance of healthy articular cartilage, and to determine how cellular heterogeneity and metabolic modulation contribute to early pathological changes leading to osteoarthritis. To attain these long-term goals, the following specific aims are proposed: 1) to isolate, characterize and utilize molecular """"""""markers"""""""" unique for different populations of bovine and human chondrocytes. the heterogeneity of the chondrocytes in articular cartilage will be defined in terms of such """"""""markers"""""""", which are considered to be synthetic or catabolic products specific for particular chondrocyte populations. 2) to isolate sub-sets of articular chondrocytes according to differences in their location in intact tissue, as well as by their metabolic differences with respect to """"""""marker"""""""" molecules. 3) to characterize the differences in matrix production and assembly, and responses to cytokines between sub-groups of human chondrocytes derived from different zones of knee and ankle cartilage, representing joints which show significant differences clinically in the incidence of osteoarthritis. 4) to compare the responses of chondrocytes from superficial and deep zones of cartilage to environmental osmotic changes, and to medium conditioned by cartilage of the same and different tissue zones. 5) to investigate mechanisms of metabolic control in chondrocytes, by examining cellular differences in receptors and mechanisms of signal transduction for Interleukin-1, using techniques of molecular biology. Bovine tissue will be used for developing new procedures and assays, before these are applied to normal human cartilage and chondrocytes. For comparative metabolic studies, chondrocytes isolated from different zones of cartilage will be cultured in suspension in agarose or alginate gels, and exposed to a variety of conditions and specific cytokines. Radiolabeled """"""""marker"""""""" molecules derived from cartilage slices or chondrocytes of specific zones will be purified and analyzed by standard biochemical methods, and antibodies raised against them, for use in separating biologically different groups of chondrocytes from the entire heterogeneous population.
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