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J. Biol. Chem., Vol. 279, Issue 19, 19502-19511, May 7, 2004

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Mechanical Compression of Cartilage Explants Induces Multiple Time-dependent Gene Expression Patterns and Involves Intracellular Calcium and Cyclic AMP^*

Jonathan B. Fitzgerald, Moonsoo Jin¶, Delphine Dean||, David J. Wood**, Ming H. Zheng**, and Alan J. Grodzinsky||

From the Biological Engineering Division, Center for Biomedical Engineering, and ^||Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 and the ^**Department of Orthopaedic Surgery, QEII Medical Centre, University of Western Australia, Nedlands, Western Australia 6009, Australia

Chondrocytes are influenced by mechanical forces to remodel cartilage extracellular matrix. Previous studies have demonstrated the effects of mechanical forces on changes in biosynthesis and mRNA levels of particular extracellular matrix molecules, and have identified certain signaling pathways that may be involved. However, the broad extent and kinetics of mechano-regulation of gene transcription has not been studied in depth. We applied static compressive strains to bovine cartilage explants for periods between 1 and 24 h and measured the response of 28 genes using real time PCR. Compression time courses were also performed in the presence of an intracellular calcium chelator or an inhibitor of cyclic AMP-activated protein kinase A. Cluster analysis of the data revealed four main expression patterns: two groups containing either transiently up-regulated or duration-enhanced expression profiles could each be subdivided into genes that did or did not require intracellular calcium release and cyclic AMP-activated protein kinase A for their mechano-regulation. Transcription levels for aggrecan, type II collagen, and link protein were up-regulated 2–3-fold during the first 8 h of 50% compression and subsequently down-regulated to levels below that of free-swelling controls by 24 h. Transcription levels of matrix metalloproteinases-3, -9, and -13, aggrecanase-1, and the matrix protease regulator cyclooxygenase-2 increased with the duration of 50% compression 2–16-fold by 24 h. Thus, transcription of proteins involved in matrix remodeling and catabolism dominated over anabolic matrix proteins as the duration of static compression increased. Immediate early genes c-fos and c-jun were dramatically up-regulated 6–30-fold, respectively, during the first 8 h of 50% compression and remained up-regulated after 24 h.

Received for publication, January 14, 2004 , and in revised form, February 11, 2004.

^* This work was supported by National Institutes of Health Grant AR33236 (to A. J. G.), National Health and Medical Research Council of Australia Grant 254742 (to D. J. W. and M. H. Z.), a Whitaker Foundation graduate fellowship (to D. D.), and a University of Western Australia Hackett Scholarship (to J. B. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Appendix and Figs. A1–A5.

^¶ Present address: The CBR Institute for Biomedical Research, Inc., Harvard Medical School, Boston, MA 02115.

To whom correspondence should be addressed: Biological Engineering Division, Massachusetts Institute of Technology, NE47-377, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-253-4969; Fax: 617-258-5239; E-mail: alg{at}mit.edu.

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