Investigator: R. Lane Smith, PhD Project Staff: Dennis R. Carter, PhD; Gary S. Beaupré, PhD; Scott A. Yerby, PhD; George Sims, MD; John Zauner, MD; Stuart B. Goodman, MD, PhD; and David J. Schurman, MD Project Category: Arthritis - 2000 Background: In arthritis loss of joint mobility results from degeneration of the cartilage surfaces at the bony ends. Destruction of cartilage follows alterations in chondrocyte metabolism that fail to preserve the original load bearing extracellular matrix. The reduced ability of cartilage to bear load results from changes in the matrix macromolecular constituents and leads to formation of erosive defects. Loss of joint function constitutes a major clinical problem that negatively impacts personal productivity, long term health and general well-being and remains a serious problem for aging Veterans Affairs patients, as well as an aging population at large. While arthroscopic techniques improve the feasibility of transplanting cells and tissue constructs into diseased joints, inappropriate joint loads may damage the implanted tissue making outcomes unacceptable. The clinical approach advanced in this proposed research is to apply external loads to precondition and restore functional loading properties to osteoarthritic cartilage explants. Results obtained in the previous funding period demonstrated that mechanical loading of human adult articular cartilage cells in vitro provided a means for stimulating aggrecan and collagen type II expression. The studies to be carried out in this proposal will develop fundamental knowledge regarding clinically applicable loading protocols by which mechanical loading can act to restore and regenerate a functional extracellular matrix in human osteoarthritic cartilage. Hypothesis: Physiological levels of mechanically induced forces that arise within cartilage play an important role in the maintenance of an intact load bearing surface in normal diarthrodial joints. The work proposed here addresses the hypothesis that repair and regeneration of articular cartilage requires specific mechanical loading regimens for generation of a functional articular cartilage extracellular matrix. The specific hypotheses to be tested are that intermittent hydrostatic pressure applied (1) in variable levels and (2) at varying frequencies will catalyze the repair of human osteoarthritic articular cartilage. Objectives: The long-term objective of this research is to provide clinically applicable methods to stimulate articular cartilage repair. This study will investigate the effects of daily treatment of human osteoarthritic cartilage with intermittent hydrostatic pressure to: (1) restore mechanical stiffness to reinstate joint function; and (2) replenish normal glycosaminoglycan content in transplantable plugs. Procedures: The objective is to apply hydrostatic pressure to full thickness explants of human osteoarthritic articular cartilage and quantify the extent of tissue repair by quantification of mechanical loading properties. The experiments will test two specific hypotheses that propose that the effects of mechanical loading with a daily regimen of intermittent hydrostatic pressure on cartilage will increase: (1) resistance to indentation loading of OA cartilage and (2) result in a restoration of glycosaminoglycan content as a specific marker of normal cartilage extracellular matrix. Funding Source: VA RR&D Merit Review |
