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J. Biol. Chem., Vol. 278, Issue 31, 28388-28394, August 1, 2003

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Shear-induced Cyclooxygenase-2 via a JNK2/c-Jun-dependent Pathway Regulates Prostaglandin Receptor Expression in Chondrocytic Cells^*,

James P. Abulencia , Renee Gaspard , Zachary R. Healy , William A. Gaarde ¶, John Quackenbush  and Konstantinos Konstantopoulos  ||

From the Department of Chemical & Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, The Institute for Genomic Research, Rockville, Maryland 20850, and ^¶Isis Pharmaceuticals, Carlsbad, California 92008

Using cDNA microarrays coupled with bioinformatics tools, we elucidated a signaling cascade regulating cyclooxygenase-2 (COX-2), a pivotal pro-inflammatory enzyme expressed in rheumatic and osteoarthritic, but not normal, cartilage. Exposure of T/C-28a2 chondrocytic cells to fluid shear results in co-regulation of c-Jun N-terminal kinase2 (JNK2), c-Jun, and COX-2 as well as concomitant downstream expression of prostaglandin receptors EP2 and EP3a1. JNK2 transcript inhibition abrogated shear-induced COX-2, EP2, and EP3a1 mRNA up-regulation as well as c-Jun phosphorylation. Functional knock-out experiments using an antisense c-Jun oligonucleotide revealed the abolition of shear-induced COX-2, EP2, and EP3a1, but not JNK2, transcripts. Moreover, inhibition of COX-2 activity eliminated mRNA upregulation of EP2 and EP3a1 induced by shear. Hence, a biochemical pathway exists wherein fluid shear activates COX-2, via a JNK2/c-Jun-dependent pathway, which in turn elicits downstream EP2 and EP3a1 mRNA synthesis.

Received for publication, February 7, 2003 , and in revised form, April 11, 2003.

^* This work was supported by a DuPont Young Professor Award (to K. K.). 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 a supplemental figure.

^|| To whom correspondence should be addressed: 3400 N. Charles St., Baltimore, MD 21218. Tel.: 410-516-6290; Fax: 410-516-5510; E-mail: kkonsta1{at}jhu.edu.

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