Nitric oxide (NO) regulates differentiation, survival, and cyclooxygenase (COX)-2 expression in articular chondrocytes. NO-induced apoptosis and dedifferentiation are mediated by p38 kinase activity and p38 kinase-independent and -dependent inhibition of protein kinase C (PKC)alpha and zeta. Because p38 kinase also activates NF-kappaB, we investigated the functional relationship between PKC and NF-kappaB signaling and the role of NF-kappaB in apoptosis, dedifferentiation, and COX-2 expression. We found that NO-stimulated NF-kappaB activation was inhibited by ectopic PKCalpha and zeta expression, whereas NO-stimulated inhibition of PKCalpha and zeta activity was not affected by NF-kappaB inhibition. Inhibition of NO-induced NF-kappaB activity did not affect inhibition of type II collagen expression but did abrogate COX-2 expression and apoptosis. Taken together, our results indicate that NO-induced inhibition of PKCalpha and activity is required for the NF-kappaB activity that regulates apoptosis and COX-2 expression but not dedifferentiation in articular chondrocytes. (C) 2003 Elsevier Science (USA). All rights reserved.