Protein kinase Cα and ζ regulate nitric oxide-induced NF-κB activation that mediates cyclooxygenase-2 expression and apoptosis but not dedifferentiation in articular chondrocytes

Abstract

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)α and ζ. Because p38 kinase also activates NF-κB, we investigated the functional relationship between PKC and NF-κB signaling and the role of NF-κB in apoptosis, dedifferentiation, and COX-2 expression. We found that NO-stimulated NF-κB activation was inhibited by ectopic PKCα and ζ expression, whereas NO-stimulated inhibition of PKCα and ζ activity was not affected by NF-κB inhibition. Inhibition of NO-induced NF-κB 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 PKCα and ζ activity is required for the NF-κB activity that regulates apoptosis and COX-2 expression but not dedifferentiation in articular chondrocytes.