Principal Investigator: R. Lane Smith, PhD Project Staff: Thomas P. Andriacchi, PhD; David J. Schurman, MD; and Stuart B. Goodman, MD, PhD Project Category: Arthritis - 2004 Soluble factors including proinflammatory cytokines, growth factors and hormones are potential mediators of the effects of altered mechanical load on changes in cartilage metabolism and the integrity of the extracellular matrix. The rationale underlying this proposal is that positive and negative effects of these families of soluble effector molecules are either stimulated or inhibited depending on the mechanical loading environment of the joint. Finite element studies of cartilage loading provide a descriptive pattern of the regional mechanical stresses and strains that may influence cartilage metabolism. Thus, completely different mechanical loading conditions such as that represented by application of fluid-induced shear stress (FISS) and intermittent hydrostatic pressure (IHP) would be predicted to significantly influence articular chondrocyte metabolism in different ways. The purpose of this proposal is to define the effects of two distinct types of mechanical load, fluid-induced shear stress and intermittent hydrostatic pressure, on proteoglycan synthesis and matrix metalloproteinase expression in human osteoarthritic articular cartilage cells. The hypothesis to be tested here is that distinct intracellular signaling pathways underlie the articular cartilage response to intermittent hydrostatic pressure and shear stress. Fundamental knowledge exists regarding the effect of the proinflammatory cytokine, interleukin-1, on the inhibition of cartilage extracellular matrix macromolecule synthesis and induction of cartilage degrading enzyme synthesis by chondrocytes. However, effects of mechanical loads on the reaction of human osteoarthritic articular chondrocytes to the inflammatory cytokine, IL-1beta, remain unclear. The specific aims examine effects of fluid-induced shear stress and intermittent hydrostatic pressure on human osteoarthritic articular chondrocyte metabolism. The experiments tested the effects of IHP and shear stress on proteoglycan synthesis in OA chondrocytes. The experiments also test whether IHP and shear stress modulate IL-1beta induced inhibition of proteoglycan synthesis. The effects of IHP and shear stress on MMP-9 expression in OA chondrocytes will be examined in the absence and presence of IL-1beta. Milestones: Three publications showing that shear s tress and intermittent hydrostatic pressure differentially influence the metabolism of osteoarthritic chondrocytes. Shear stress induced apoptosis and decreased matrix protein expression whereas hydrostatic pressure provided a functional stimulus for increased matrix synthesis and could attenuate effects of shear stress on matrix protein expression. Hydrostatic pressure provided a protective effect against inflammatory agents, such as bacterial lipopolysaccharide. Funding Source: NIH Funding Status: Active |
