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Biomechanical Signals Suppress TAK1 Activation to Inhibit NF-B Transcriptional Activation in Fibrochondrocytes¹

Shashi Madhavan^*, Mirela Anghelina^*, Danen Sjostrom^*, Anar Dossumbekova^*, Denis C. Guttridge and Sudha Agarwal^2,*,

^* Biomechanics and Tissue Engineering Laboratory, Section of Oral Biology, Department of Molecular Virology, Immunology and Medical Genetics, Department of Orthopedics, The Ohio State University, Columbus Ohio 43210

Exercise/joint mobilization is therapeutic for inflammatory joint diseases like rheumatoid and osteoarthritis, but the mechanisms underlying its actions remain poorly understood. We report that biomechanical signals at low/physiological magnitudes are potent inhibitors of inflammation induced by diverse proinflammatory activators like IL-1, TNF-, and lipopolysaccharides, in fibrochondrocytes. These signals exert their anti-inflammatory effects by inhibiting phosphorylation of TAK1, a critical point where signals generated by IL-1, TNF-, and LPS converge to initiate NF-B signaling cascade and proinflammatory gene induction. Additionally, biomechanical signals inhibit multiple steps in the IL-1-induced proinflammatory cascade downstream of IB kinase activation to regulate IB and IB degradation and synthesis, and promote IB shuttling to export nuclear NF-B and terminate its transcriptional activity. The findings demonstrate that biomechanical forces are but another important signal that uses NF-B pathway to regulate inflammation by switching the molecular activation of discrete molecules involved in proinflammatory gene transcription.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health by Grants AR04878, DE15399, AT00646, and HD40939.

² Address correspondence and reprint requests to Dr. Sudha Agarwal, The Ohio State University, 4171 Postle Hall, 305 West 12th Avenue, Columbus, OH 43210. E-mail address: Agarwal.61{at}osu.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; OA, osteoarthritis; COX, cyclooxygenase; MMP, matrix metalloproteinase; FC, fibrochondrocyte; IKK, IB kinase; TMJ, temporomandibular joint; CTS, cyclic tensile strain; iNOS, inducible NO synthase.

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