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J. Biol. Chem., Vol. 278, Issue 43, 42448-42456, October 24, 2003

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Actin Cytoskeletal Architecture Regulates Nitric Oxide-induced Apoptosis, Dedifferentiation, and Cyclooxygenase-2 Expression in Articular Chondrocytes via Mitogen-activated Protein Kinase and Protein Kinase C Pathways^*

Song-Ja Kim, Sang-Gu Hwang, Il-Chul Kim, and Jang-Soo Chun¶

From the Department of Biological Science, Kongju National University, Gongju, Chungnam 314-701 and the Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, Korea

Nitric oxide (NO) in articular chondrocytes regulates differentiation, survival, and inflammatory responses by modulating ERK-1 and -2, p38 kinase, and protein kinase C (PKC) and . In this study, we investigated the effects of the actin cytoskeletal architecture on NO-induced dedifferentiation, apoptosis, cyclooxygenase (COX)-2 expression, and prostaglandin E₂ production in articular chondrocytes, with a focus on ERK-1/-2, p38 kinase, and PKC signaling. Disruption of the actin cytoskeleton by cytochalasin D (CD) inhibited NO-induced apoptosis, dedifferentiation, COX-2 expression, and prostaglandin E₂ production in chondrocytes cultured on plastic or during cartilage explants culture. CD treatment did not affect ERK-1/-2 activation but blocked the signaling events necessary for NO-induced dedifferentiation, apoptosis, and COX-2 expression such as activation of p38 kinase and inhibition of PKC and -. CD also suppressed activation of downstream signaling of p38 kinase and PKC, such as NF-B activation, p53 accumulation, and caspase-3 activation, which are necessary for NO-induced apoptosis. NO production in articular chondrocytes caused down-regulation of phosphatidylinositol (PI) 3-kinase and Akt activities. The down-regulation of PI 3-kinase and Akt was blocked by CD treatment, and the CD effects on apoptosis, p38 kinase, and PKC and - were abolished by the inhibition of PI 3-kinase with LY294002. Our results collectively indicate that the actin cytoskeleton mediates NO-induced regulatory effects in chondrocytes by modulating down-regulation of PI 3-kinase and Akt, activation of p38 kinase, and inhibition of PKC and -

Received for publication, May 9, 2003 , and in revised form, July 30, 2003.

^* This work was supported by the National Research Laboratory Program M1-0104-00-0064 (Korea Ministry of Science and Technology) and Rheumatoid Research Center Program R11-2002-098-04005-0 (Korea Science and Engineering Foundation). 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, Kwangju 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}kjist.ac.kr.

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