Mechanisms and functional implications of aggrecan catabolism in cartilage and meniscal fibrocartilage.

摘要

Articular cartilage and fibrocartilage participate in bone-to-bone load transfer and provide low-friction surfaces for smooth joint motion. These tissues are susceptible to traumatic injury and arthritic disease, and their degeneration leads to loss of joint function and pain for the patient. Cells that reside in cartilage and fibrocartilage normally remodel the extracellular matrix in response to biochemical and mechanical signals, and progression of joint disease is characterized by excessive cell-mediated degradation of the tissues. In addition, pathologic changes in tissue composition typically result in loss of tissue material properties. Differences between cartilage and fibrocartilage matrix composition, cell metabolism, and mechanical function suggest that the mechanisms and functional implications of normal and pathologic remodeling may also be different. The goal of this work was to examine tissue-specific responses to catabolic and anabolic stimuli with respect to production and processing of aggrecan, a structural matrix molecule in cartilage and fibrocartilage. Studying matrix remodeling can contribute to our understanding of arthritis, and may give insight into therapeutic approaches for the repair or replacement of degenerative joint tissues.; As an in vitro model of cartilage degradation, explanted cartilage and fibrocartilage were subjected to stimulation with a proinflammatory cytokine. Selective protease inhibitors were used to perturb matrix remodeling, antibodies raised to aggrecan neoepitopes were used to characterize protease activity, and compression and torsion tests were used to measure tissue material properties. Time course experiments showed that protease inhibitors delayed, but did not block destructive aggrecan remodeling in cartilage. In contrast, fibrocartilage cultures treated with a broad-spectrum metalloproteinase inhibitor were protected from degradation as indicated by biochemical assay and mechanical testing. For the final experiments, chondrocytes and fibrochondrocytes were suspended in agarose and stimulated with an anabolic growth factor. The cell types exhibited similar patterns of aggrecan processing, though proteoglycan biosynthesis and construct material properties were substantially higher in the chondrocyte cultures. Collectively, these results reveal intrinsic differences in tissue-specific cellular responses to catabolic and anabolic cytokines that may underlie some aspects of arthritic joint degeneration.