Articular cartilage functions as a weight bearing, wear-resistant material in synovial joints. The ability of cartilage to withstand compressive, tensile and shear forces depends critically on the composition and structural integrity of its extracellular matrix. The maintenance of a functionally intact matrix requires the coordinated synthesis, assembly, degradation of proteoglycans, collagens, and other matrix molecules. The regulation of these metabolic processes in vivo appears to involve a combination of cell biological and physical mechanisms. Clinical observations and studies in vivo suggest that joint loading and motion can induce a wide range of metabolic responses in cartilage. While some degree of """"""""normal"""""""" joint loading appears to promote structural adaptation, """"""""abnormal"""""""" mechanical forces predispose cartilage to degeneration. The physical and biological processes responsible for these alterations are not fully understood and are difficult to identify in vivo. As a result, cartilage explant systems have become increasingly important for studies aimed at understanding the mechanisms by which physical forces may regulate cartilage metabolism. The applicants have developed an in vitro model system to characterize the metabolic response of cartilage explants to a broad range of static and dynamic mechanical loads. Precisely controlled static and dynamic compression can be applied to multiple disks of cartilage. They observed that the metabolic response in vitro displays many of the attributes of the above in vivo studies. Their model provides the framework for examining the biophysical mechanisms involved in modulating synthesis, assembly, and degradation of cartilage matrix molecules during and after application of static and dynamic compression. In addition, precise but disruptive long-term mechanical loading of adult cartilage explants in various culture configurations may yield insights into the direct role of biophysical mechanisms in cartilage degeneration. Previously, the investigators focused on the general effects of compression on the synthesis, assembly, and loss of 35S- and 3H-labeled macromolecules. They now propose to extend these studies to quantify the effects of static and dynamic mechanical compression on the synthesis and catabolism of specific target molecules within the matrix that are responsible for the functional behavior of cartilage, namelyaggrecan, link protein, hyaluronan and collagen. They will investigate the effects of compression on synthesis and catabolism of these molecules with methods and probes which have become available as a result of studies in cartilage biology, biophysics, and bioengineering, in order to address these fundamental questions.
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