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J. Biol. Chem., Vol. 280, Issue 33, 29780-29787, August 19, 2005

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c-Jun/Activator Protein-1 Mediates Interleukin-1-induced Dedifferentiation but Not Cyclooxygenase-2 Expression in Articular Chondrocytes^*

Sang-Gu Hwang, Sung-Sook Yu, Haryoung Poo, and Jang-Soo Chun¶

From the Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea and Proteome Research Laboratory, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-600, Korea

Interleukin (IL)-1 is a major catabolic pro-inflammatory cytokine involved in cartilage destruction-associated processes, such as loss of the differentiated chondrocyte phenotype (dedifferentiation) and inflammation. Here, we investigated the role of c-Jun and activator protein-1 (AP-1) in IL-1-induced dedifferentiation and cyclooxygenase (COX)-2 expression in primary cultured chondrocytes. IL-1 induced expression and transient phosphorylation of c-Jun in primary cultured chondrocytes. Ectopic expression of c-Jun was sufficient to cause dedifferentiation, whereas expression of dominant negative c-Jun blocked IL-1-induced dedifferentiation. Interestingly, modulation of c-Jun expression did not affect IL-1-induced COX-2 expression. Further experiments revealed that c-Jun phosphorylation was mediated by c-Jun N-terminal kinase and was required for IL-1-induced dedifferentiation but not COX-2 expression. Consistent with its ability to induce phosphorylation of c-Jun, IL-1 caused transient activation of AP-1, which is necessary for IL-1-induced dedifferentiation. IL-1 treatment suppressed expression of Sox-9, a major transcription factor that regulates type II collagen expression. Inhibition of c-Jun N-terminal kinase or AP-1 reversed IL-1-induced suppression of Sox-9, and ectopic expression of c-Jun was sufficient to cause suppression of Sox-9. Our results collectively suggest that IL-1 suppresses type II collagen expression in articular chondrocytes by inducing expression and phosphorylation of c-Jun, AP-1 activation, and subsequent suppression of Sox-9.

Received for publication, October 18, 2004 , and in revised form, May 11, 2005.

^* This work was supported by the National Research Laboratory Program (M1-0104-00-0064) from the Korea Ministry of Science and Technology, the Basic Research Program of the Korea Science and Engineering Foundation (R01-2003-000-10154-0/R02-2004-000-10015-0), and Korea Research Institute of Bioscience and Biotechnology Initiative Program (KGS0210512). 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.

^¶ To whom correspondence should be addressed: Dept. of Life Science, Gwangju Institute of Science and Technology, Buk-Gu, Gwangju 500-712, Korea. Tel.: 82-62-970-2497; Fax: 82-62-970-2484; E-mail: jschun{at}gist.ac.kr.

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