published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

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Changes in the structural organization of cartilage and synovial tissue, or in the macromolecules produced by their cells, alter the properties of the tissues. Elucidation of the changes under controlled experimental conditions could make a significant contribution to the understanding of the pathogenesis of arthritis. To this end a model system has been developed to study proteoglycan and collagen regeneration in porcine articular cartilage and synovial tissue: partially depleted of matrix by exogenous enzyme(s), the tissues were maintained in organ culture, the medium consisting of Dulbecco's modification of Eagle's medium and 15% rabbit serum, and the responses of the chondrocytes and synoviocytes studied biochemically and histologically. Cleavage of proteoglycan core protein in cartilage explants by trypsin, equivalent to the disruption occurring in joint inflammation, induced glycosaminoglycan synthesis. The chondrocytes, particularly of the mid and hypertrophic zones, acquiring a basophilic territorial matrix and eventually an interterritorial matrix, which replaced the ex vivo material. Further damage to collagen by bacterial collagenase induced collagen synthesis, and enhanced glycosaminoglycan synthesis, but hyaluronic acid disruption proved partially inhibitory to recovery, the interterritorial matrix being less basophilic than comparable trypsinized explants. ³⁵SO₄ uptake by depleted explants showed a similar but sustained rate of glycosaminoglycan synthesis compared with untreated explants. The effects of corticosteroids, currently used for the temporary palliation of joint inflammation, on the regeneration processes were studied. The hydrolytic potential of the cultures and the frequency of medium changes had a profound effect on biologically active cortisol levels when cortisol succinate was present. Lower than physiological levels of cortisol (≤2.76 x 10^-7M) promoted glycosaminoglycan synthesis in all disrupted explants except those with cleaved hyaluronic acid chains. During the later stages of culture, in the presence of cortisol, (≤2.76 x 10-7M), the interterritorial glycosaminoglycan concentration increased. Whether collagen fibres were disrupted or not, collagen synthesis was evident, although with pharmacological concentrations of steroid (≤2.76 x 10^-6 M) all synthetic processes were increasingly inhibited. Exogenous trypsin induced extensive resorption of collagen fibres in minced synovial tissue, probably by activation of synovial collagenase. The destruction was partially reduced with trypsin inhibitor or cortisol. In areas of degradation macrophage-like cells accumulated but with early removal of trypsin, despite loss of collagen, fibroblast-like cells accumulated at the base of the explants with synthesized pericellular collagen evident. Collagen release into the medium was measured by an improved hydroxyproline assay designed to reduce interference from serum proteins. Although physiological doses of cortisol (≤2.76 x 10-7 M) enhanced collagen synthesis by, and the development of, the fibroblastic cells, extensive tissue repair was not observed, merely the formation of a cell population in the Millipore membrane. This model of tissue regeneration, remodelling and repair leads to the conclusion that within the arthritic joint the chondrocyte has the potential to rapidly attempt to repair damaged matrix, the extent of synthesis being proportional to the extent and type of matrix disruption. The chondrocyte responds by synthesizing glycosaminoglycans, that aggregate within the matrix, and collagen, with cortisol, at below physiological concentrations, enhancing this regeneration. Synovial tissue did not recover from disruption although the synoviocytes, on reversion to fibroblast-like cells, accumulated new collagen.

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LD2668 .T4 1949 W52 / Master of Science

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Thesis (M.S.) in Biochemistry--University of Maine, 2009. / Includes vita. Includes bibliographical references (leaves 44-48).

Thesis (M.S.)--Brigham Young University. Dept. of Exercise Sciences, 2008. / Includes bibliographical references.