Effects of shear stress on articular chondrocyte metabolism

The articular cartilage of diarthrodial joints experiences a variety of str esses, strains and pressures that result from normal activities of daily li ving. Tn normal cartilage, the extracellular matrix exists as a highly orga nized composite of specialized macromolecules that distributes loads at: th e bony ends. The chondrocyte response to mechanical loading is recognized a s an integral component in the maintenance of articular cartilage matrix ho meostasis. With inappropriate mechanical loading of the joint, as occurs wi th traumatic injury, ligament instability, bony malalignment or excessive w eight bearing, the cartilage exhibits manifestations characteristic of oste oarthritis. Breakdown of cartilage in osteoarthritis involves degradation o f the extracellular matrix macromolecules and decreased expression of chond rocyte proteins necessary for normal joint function. Osteoarthritic cartila ge often exhibits increased amounts of type I collagen and synthesis of pro teoglycans characteristic of immature cartilage. The shift in cartilage phe notype in response to altered load yields a matrix that fails to support no rmal joint function. Mathematical modeling and experimental studies in animal models confirm an association between altered loading of diarthrotic joints and arthritic cha nges. Both types of studies implicate shear forces as a critical component in the destructive profile. The severity of cartilage destruction in respon se to altered loads appears linked to expression of biological factors infl uencing matrix integrity and cellular metabolism. Determining how shear str ess alters chondrocyte metabolism is fundamental to understanding how to li mit matrix destruction and stimulate cartilage repair and regeneration. At present, the precise biochemical and molecular mechanisms by which shear forces alter chondrocyte metabolism from a normal to a degenerative phenot ype remain unclear. The results presented here address the hypothesis that articular chondrocyte metabolism is modulated by direct effects of shear fo rces that act on the cell through mechanotransduction processes. The purpos e of this work is to develop critical knowledge regarding the basic mechani sms by which mechanical loading modulates cartilage metabolism in health an d disease. This presentation will describe the effects of using fluid induced shear st ress as a model system for stimulation of articular chondrocytes in vitro. The fluid induced shear stress was applied using a cone viscometer system t o stimulate all the cells uniformly under conditions of minimal turbulence. The experiments were carried using high-density primary monolayer cultures of normal and osteoarthritic human and normal bovine articular chondrocyte s. The analysis of the cellular response included quantification of cytokin e release, matrix metalloproteinase expression and activation of intracellu lar signaling pathways. The data presented here show that articular chondro cytes exhibit a dose- and time-dependent response to shear stress that resu lts in the release of soluble mediators and extracellular matrix macromolec ules. The data suggest that the chondrocyte response to mechanical stimulat ion contributes to the maintenance of articular cartilage homeostasis in vi vo.