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J. Biol. Chem., Vol. 278, Issue 51, 50940-50948, December 19, 2003

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Mechanical Regulation of Mitogen-activated Protein Kinase Signaling in Articular Cartilage^*

Paul J. Fanning¶, Gregory Emkey, Robert J. Smith||, Alan J. Grodzinsky**, Nora Szasz**, and Stephen B. Trippel

From the Massachusetts General Hospital, Orthopædic Research Laboratories, Boston, Massachusetts 02114, theHarvard Medical School, Boston, Massachusetts 02115, the^||Joslin Diabetes Center, Boston, Massachusetts 02215, and the^**Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Articular chondrocytes respond to mechanical forces by alterations in gene expression, proliferative status, and metabolic functions. Little is known concerning the cell signaling systems that receive, transduce, and convey mechanical information to the chondrocyte interior. Here, we show that ex vivo cartilage compression stimulates the phosphorylation of ERK1/2, p38 MAPK, and SAPK/ERK kinase-1 (SEK1) of the JNK pathway. Mechanical compression induced a phased phosphorylation of ERK consisting of a rapid induction of ERK1/2 phosphorylation at 10 min, a rapid decay, and a sustained level of ERK2 phosphorylation that persisted for at least 24 h. Mechanical compression also induced the phosphorylation of p38 MAPK in strictly a transient fashion, with maximal phosphorylation occurring at 10 min. Mechanical compression stimulated SEK1 phosphorylation, with a maximum at the relatively delayed time point of 1 h and with a higher amplitude than ERK1/2 and p38 MAPK phosphorylation. These data demonstrate that mechanical compression alone activates MAPK signaling in intact cartilage. In addition, these data demonstrate distinct temporal patterns of MAPK signaling in response to mechanical loading and to the anabolic insulin-like growth factor-I. Finally, the data indicate that compression coactivates distinct signaling pathways that may help define the nature of mechanotransduction in cartilage.

Received for publication, May 15, 2003 , and in revised form, September 2, 2003.

^* This work was supported by National Institutes of Health Grants AR45749 (to S. B. T.) and AR33236 (to A. J. G.). 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.

^¶ Present address: Depts. of Orthopedics, Surgery, and Cell Biology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Tel.: 508-856-3054; Fax: 508-856-6953; E-mail: paul.fanning{at}umassmed.edu.

To whom correspondence should be addressed: Indiana University School of Medicine, Dept. of Orthopedic Surgery, 541 Clinical Dr., Indianapolis, IN 46202. Tel.: 317-274-7913; Fax: 317-274-3702; E-mail: strippel{at}iupui.edu.

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