Degenerative and inflammatory disorders of cartilage such as osteoarthritis and rheumatoid arthritis are debilitating diseases which affect large numbers of people. Cartilage functions as a mechanical bearing material, and the mechanical integrity of the tissue is a reflection of the architecture and composition of cartilage matrix macromolecules. Human interleukin-1beta (IL-1beta) promotes cartilage destruction and bone resorption, and reduces the rate at which matrix glycosaminoglycans (GAGs) are synthesized. In culture, mechanical forces have been shown to enhance or diminish the rate of GAG synthesis, depending on the magnitude and frequency of loading. The goals of this project are to determine the coupled effects of compressive mechanical loading and IL-1beta on the mechanical properties (dynamic and static stiffness) and biochemical properties (GAG loss and synthesis) of cartilage in explant culture. It will be determined if mechanical loads can exacerbate or ameliorate the loss of tissue GAG seen with IL-1beta alone. Moreover, the utility of the naturally occurring IL-1 receptor antagonist (IL-1ra) in blocking the effects of IL-1beta will be evaluated in the presence of applied mechanical loading. In addition, a mutant protein (IL-1betaR-G) which in non- cartilage systems exhibits a partial defect in signal transduction (including minimal stimulation of prostromelysin and procollagenase mRNA) will be evaluated to determine its effects on cartilage. GAG synthesis and loss and tissue mechanical properties will be measured while cartilage is cultured in one of four conditions: (1) no dynamic mechanical loading and no IL-1; (2) no loading with IL-1; (3) loading but no IL-1; and (4) loading with IL-1. To evaluate the physical processes involved in eliciting the cartilage response, two mechanical loading regimens are proposed: one in which a large deformation is slowly applied, leading to substantial volume change during each cycle; the other in which a small deformation is rapidly applied, leading to little volume change, but high hydrostatic pressures during each cycle. Finally, the effectiveness of IL-1ra in blocking IL-1 effects and of IL-1R-G in inducing IL-1-like effects will be evaluated to better understand the mechanisms involved in IL-1-mediated and force- mediated changes in cartilage metabolism. The approach used in this work has not been previously reported. As the joints of arthritic patients are both loaded and potentially exposed to IL-1 or other cytokines, this work will provide significant and information which is critical for our understanding of the progression of arthritic diseases.
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