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J. Biol. Chem. 278 (17): 15319-15325

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Non-steroidal Anti-inflammatory Drugs Inhibit Nitric Oxide-induced Apoptosis and Dedifferentiation of Articular Chondrocytes Independent of Cyclooxygenase Activity*

Joo-Byoung YoonDagger , Song-Ja KimDagger , Sang-Gu HwangDagger , Sunghoe ChangDagger , Shin-Sung Kang§, and Jang-Soo ChunDagger ||

From the Dagger  Department of Life Science, Kwangju Institute of Science and Technology; Buk-Gu, Gwangju 500-712, Korea, and § Department of Biology, Kyungpook National University, Daegu 702-701, Korea

Nitric oxide (NO) causes apoptosis and dedifferentiation of articular chondrocytes by the modulation of extracellular signal-regulated kinase (ERK), p38 kinase, and protein kinase C (PKC) alpha  and -zeta . In this study, we investigated the effects and mechanisms of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, in NO-induced apoptosis and dedifferentiation of articular chondrocytes. We found that all of the examined NSAIDs inhibited apoptosis and dedifferentiation. NO production in chondrocytes caused activation of ERK-1/2 and p38 kinase, which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKCalpha and -zeta independent of and dependent on, respectively, p38 kinase, which is required for apoptosis and dedifferentiation. Among the signaling molecules modulated by NO, NSAIDs blocked NO-induced activation of p38 kinase, potentiated ERK activation, and blocked inhibition of PKCalpha and -zeta . NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NFkappa B activation, p53 accumulation, and caspase-3 activation. The inhibitory effects of NSAIDs on apoptosis and dedifferentiation were independent of the inhibition of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE2 production or exogenous PGE2 did not affect NO-induced apoptosis and dedifferentiation. Taken together, our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKCalpha and -zeta in a manner independent of their ability to inhibit COX-2 and PGE2 production.

* This work was supported by the National Research Laboratory Program (M1-0104-00-0064) from the Korea Ministry of Science and Technology and the Interdisciplinary Research Project (1999-2-207-004-5) from the Korea Science and Engineering Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Funded by Korea Research Foundation Grant KRF-2000-015-DP0352.

|| To whom correspondence should be addressed. Tel.: 82-62-970-2497; Fax: 82-62-970-2484; E-mail: jschun@kjist.ac.kr.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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