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Cyclic Tensile Stress Exerts Antiinflammatory Actions on Chondrocytes by Inhibiting Inducible Nitric Oxide Synthase¹

Robert Gassner^*,, Michael J. Buckley, Helga Georgescu, Rebecca Studer, Maja Stefanovich-Racic, Nicholas P. Piesco^§, Christopher H. Evans and Sudha Agarwal^2,§

^* Department of Oral and Maxillofacial Surgery, University of Innsbruck Medical Center, Innsbruck, Austria; Departments of Oral and Maxillofacial Surgery, Orthopedic Surgery, and ^§ Oral Medicine and Pathology, University of Pittsburgh, Pittsburgh, PA 15261

Continuous passive motion manifests therapeutic effects on inflamed articular joints by an as-yet-unknown mechanism. Here, we show that application of cyclic tensile stress (CTS) in vitro abrogates the catabolic effects of IL-1ß on chondrocytes. The effects of CTS are mediated by down-regulation of IL-1ß-dependent inducible NO production, and are directly attributed to the inhibition of inducible NO synthase (iNOS) mRNA expression and protein synthesis. The inhibition of iNOS induction by CTS is paralleled by abrogation of IL-1ß-induced down-regulation of proteoglycan synthesis. Furthermore, CTS inhibits iNOS expression and up-regulates proteoglycan synthesis at concentrations of IL-1ß frequently observed in inflamed arthritic joints, suggesting that the actions of CTS may be clinically relevant in suppressing the sustained effects of pathological levels of IL-1ß in vivo. These results are the first to demonstrate that mechanisms of the intracellular actions of CTS in IL-1ß-activated chondrocytes are mediated through inhibition of a key molecule in the signal transduction pathway that leads to iNOS expression.

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