Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate the pain and inflammation of arthritis through inhibition of cyclooxygenase (COX) and a consequent reduction in prostaglandin production. NSAIDs also affect cartilage production by articular chondrocytes and protect chondrocytes from dedifferentiation and apoptosis, processes implicated in the pathophysiology of arthritis. Yoon et al. investigated the mechanisms by which NSAIDs inhibit dedifferentiation and apoptosis in response to nitric oxide (NO), which activates multiple signaling pathways with differing effects on chondrocyte apoptosis and dedifferentiation. The authors used sodium nitroprusside to stimulate NO production and to trigger dedifferentiation and apoptosis in primary cultures of rabbit articular chondrocytes and three-dimensional cultures of rabbit cartilage explants. Various NSAIDs inhibited dedifferentiation and apoptosis under both conditions. The NSAID indomethacin enhanced activation of extracellular signal-regulated protein kinases (ERK1 and 2) as assessed by Western analysis, which would be expected to promote NO-mediated dedifferentiation but inhibit NO-mediated apoptosis. Indomethacin inhibited NO-mediated activation of p38 kinase, as determined by an in vitro kinase assay, which would also be expected to promote NO-mediated dedifferentiation and inhibit NO-mediated apoptosis. Indomethacin also blocked NO-mediated inhibition of protein kinase C (PKC) α and ζ, effects that would be expected to inhibit both NO-mediated dedifferentiation and apoptosis. Pharmacological inhibition of COX-2, as well as treatment with prostaglandin E2, indicated that NSAID inhibition of NO-mediated apoptosis and dedifferentiation was independent of effects on COX-2 activity and prostaglandin synthesis. Thus, NSAIDs appear to inhibit chondrocyte apoptosis and dedifferentiation through multiple signaling pathways distinct from their inhibition of COX pathway-dependent pain and inflammation.
J.-B. Yoon, S.-J. Kim, S.-G. Hwang, S. Chang, S.-S. Kang, Non-steroidal anti-inflammatory drugs inhibit nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes independent of cyclooxygenase activity. J. Biol. Chem. 278, 15319-15325 (2003). [Abstract] [Full Text]