Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocytecultures

The p38 MAP kinase inhibitor, SE 242235, was evaluated for its effects on t he metabolism of bovine and human cartilage and primary chondrocyte culture s. SE 242235 had no effect on proteoglycan synthesis (PG) in bovine articul ar cartilage explants (BAC), as measured by [S-35]-sulfate incorporation in to glycosaminoglycans (GAGs). In addition, the compound had no effect on IL -1 alpha -induced GAG release from these cultures. However, there was a pot ent, dose-dependent inhibition of nitric oxide (NO) release from IL-1 alpha -stimulated BAC with an IC50 of approximately 0.6 muM, with similar effect s observed in primary chondrocytes. The effect on BAC was time dependent, a nd mechanistically did not appear to be the result of inhibition of protein kinase C (PKC), protein kinase A (PKA) or MEK-1. The effect on NO release in bovine chondrocytes was at the level of inducible nitric oxide synthase (iNOS) gene expression, which was inhibited at similar concentrations as ni trite production. In primary human chondrocytes, IL-1 beta induction of p38 MAP kinase was inhibited by SE 242235 with an IC50 of approximately 1 muM. Surprisingly, however, treatment of IL-beta -stimulated human cartilage or chondrocytes with SE 242235 did not inhibit either NO production or the in duction of INOS. On the other hand, the natural product hymenialdisine (HYM ), a protein tyrosine kinase (PTK) inhibitor, inhibited NO production and I NOS in both species. In contrast to the differential control of iNOS, PGE(2 ) was inhibited by SE 242235 in both IL-1-stimulated bovine and human chond rocyte cultures. These studies indicate that there are species differences in the control of INOS by p38 inhibitors and also that different pathways m ay control IL-1-induced proteoglycan breakdown and NO production. (C) 2000 OsteoArthritis Research Society International.