Abstract

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 NFkappaB 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 E(2) (PGE(2)) production, as evidenced by the observation that specific inhibition of COX-2 activity and PGE(2) production or exogenous PGE(2) 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 PGE(2) production.

Highlights

  • Chondrocytes are a unique cell type in which the differentiated phenotype is reversible

  • All of the examined non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, ketoprofen, ibuprofen, sulindac sulfide, and flurbiprofen, blocked chondrocyte apoptosis in a dose-dependent manner. These results indicate that NSAIDs block Nitric oxide (NO)-induced apoptosis of articular chondrocytes

  • High levels of nitrite/nitrate are found in the synovial fluid and serum of arthritis patients [37], and it has been shown that NO causes loss of a differentiated phenotype and apoptosis of articular chondrocytes [6, 7, 12,13,14]

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Summary

Introduction

Chondrocytes are a unique cell type in which the differentiated phenotype is reversible. Our results indicate that NSAIDs block NO-induced apoptosis and dedifferentiation of articular chondrocytes by the modulation of ERK, p38 kinase, and PKC␣ and -␨ in a manner independent of their ability to inhibit COX-2 and PGE2 production.

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