Investigator: R. Lane Smith, PhD Project Staff: Dennis R. Carter, PhD; Gary S. Beaupré, PhD; Scott A. Yerby, PhD; Andrew R. Hoffman, MD; Michael M. Ward, MD; George Sims, MD; John Zauner, MD; Stuart B. Goodman, MD, PhD; and David J. Schurman, MD Project Category: Arthritis - 2000 Background: In osteoarthritis (OA), articular cartilage destruction follows changes in cartilage cell metabolism that alters the load bearing properties of the extracellular matrix and culminates in loss of joint function. OA chondrocytes exhibit a shift in collagen synthesis with diminished production of the hyaline cartilage type II collagen and relatively more type I collagen. OA chondrocytes also exhibit increased release of large, chondroitin-rich proteoglycans characteristic of immature cartilage. Altering the cartilage phenotype produces a matrix less effective as a loading bearing material that shows a loss of integrity of the cartilage surface with continued loading. Progressive degeneration of cartilage ultimately manifests as erosive osteoarthritis with severely painful joints that function poorly or not at all. The loss of joint function results in severe impairment of daily activity and is a major clinical problem that seriously impacts personal productivity, long term health and general well-being. Hypothesis: Physiological levels of intermittent hydrostatic pressure that occur within cartilage as the major diarthrodial joint are loaded reach levels up to 10 MPa. Intermittent hydrostatic pressure is an important determinant of the stress modes that occur with mechanical loading of normal diarthrodial joints during daily activity. The work proposed here addresses the hypothesis that activation of processes important for repair and regeneration of articular cartilage requires selective mechanical loading regimens to induce genetic expression important for a stable and functional cartilage matrix. The specific hypotheses to be tested are that precisely controlled interval loading with variable high levels and varying frequencies of intermittent hydrostatic pressure will stimulate phenotypic expression of articular cartilage extracellular matrix macromolecules. Objectives: This study will investigate how intermittent hydrostatic pressure applied over precisely defined loading periods serves as a stimulus for articular cartilage repair and regeneration. The experiments test effects of applying intermittent hydrostatic pressure on human osteoarthritic cartilage cells to: (1) induce expression of the large aggregating proteoglycans, aggrecans and type II collagen; (2) decrease expression of the matrix metalloproteinases; and (3) act in concert with the effects of serum-derived and purified growth factors. Procedures: The experiments will apply hydrostatic pressure to primary cultures of human articular chondrocytes and quantify the cellular response through extracellular matrix protein expression. Three experimental aims will test effects of interval loading using: (1) varying physiological levels (1, 5 and 10 MPa); and (2) frequencies (0.1, 1 and 10 Hz) of hydrostatic pressure on (a) aggrecan expression, and type II collagen expression (b) expression of cartilage degrading matrix metalloproteinases and (c) the interaction between hydrostatic pressure and cartilage stimulating insulin-like growth factor I and basic fibroblast growth factor. Recent Publications: Lee M, Trindade MCD, T Ikenoue T, EY Lin EY, Schurman DJ, Goodman SB, RL Smith RL: Differential expression of nitric oxide in human chondrocytes during intermittent hydrostatic pressure or shear stress. Transactions of the 19th Annual Meeting of the Society for Physical Regulation in Biology and Medicine, January, 2000 Lin EY, Trindade MCD, Ikenoue T, Lee M, Goodman SB, Schurman DJ, Smith RL: Intermittent hydrostatic pressure stimulates expression of aggrecan and type II collagen mRNA in human osteoarthritic chondrocytes in vitro. Transactions of the 19th Annual Meeting of the Society for Physical Regulation in Biology and Medicine, January, 2000 Trindade MCD, Shida J, Ikenoue T, Lee MS, Lin EY, Shah SN, Yerby SA, Goodman SB, Schurman DJ, Smith RL: Effect of intermittent hydrostatic pressure on osteoarthritic chondrocyte pro-inflammatory mediator and matrix metalloproteinase release in vitro. Transactions of the 19th Annual Meeting of the Society for Physical Regulation in Biology and Medicine, January, 2000 Ikenoue T, Lee M, Lin EY, Trindade MCD, Schurman DJ, Goodman SB, RL Smith RL: Modulation of aggrecan expression in normal human articular chondrocytes by intermittent hydrostatic pressure. Transactions of the 19th Annual Meeting of the Society for Physical Regulation in Biology and Medicine, January, 2000 Trindade MCD, Shida J, Yerby S, Yaszay B, Goodman SB, Schurman DJ, Smith RL: Intermittent hydrostatic pressure inhibits interleukin-6 and monocyte chemoattractant protein-1 expression by human osteoarthritic chondrocytes in vitro. Submitted to the Journal of Orthopaedic Research. Funding Source: VA Medical Merit Review |
