Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of the regulation of cyclooxygenase activity

doi:10.1074/jbc.M212520200

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of the regulation of cyclooxygenase activity

Joo-Byung Yoon, Song-Ja Kim, Sang-Gu Hwang, Sunghoe Chang, Shin-Sung Kang, and Jang-Soo Chun

Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712

Corresponding Author: jschun{at}kjist.ac.kr

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, both of which oppositely regulate apoptosis and dedifferentiation. NO production also caused inhibition of PKC $alpha$ and $zeta$ independent of and dependent on p38 kinase, respectively, that 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 PKC $alpha$ and $zeta$ . NSAIDs also inhibited some of the apoptotic signaling that is downstream of p38 kinase and PKC, such as NF $kappa$ 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 PKC $alpha$ and $zeta$ in a manner independent of their ability to inhibit COX-2 and PGE2 production.

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