TY - JOUR T1 - Phenyl <em>N-tert</em>-Butylnitrone Down-Regulates Interleukin-1β-Stimulated Matrix Metalloproteinase-13 Gene Expression in Human Chondrocytes: Suppression of c-Jun NH<sub>2</sub>-Terminal Kinase, p38-Mitogen-Activated Protein Kinase and Activating Protein-1 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 981 LP - 988 DO - 10.1124/jpet.102.048611 VL - 305 IS - 3 AU - Salahuddin Ahmed AU - Ayesha Rahman AU - Absarul Hasnain AU - Victor M. Goldberg AU - Tariq M. Haqqi Y1 - 2003/06/01 UR - http://jpet.aspetjournals.org/content/305/3/981.abstract N2 - Cytokine-mediated induction and overexpression of matrix metalloproteinases (MMPs) is recognized as an important factor in the pathogenesis of arthritis. Interleukin (IL)-1β is a proinflammatory cytokine that is known to superinduce the expression and production of MMP-13 in many cell types. Phenyl N-tert-butylnitrone (PBN), a spin trap agent, inhibited the IL-1β-induced expression of MMP-13 in human osteoarthritis (OA) chondrocytes. Down-regulation of MMP-13 expression correlated with the inhibition of mitogen-activated protein kinase (MAPK) subgroups c-Jun NH2-terminal kinase (JNK) and p38-MAPK activation, accumulation of phospho-c-jun, and the DNA binding activity of activating protein-1 (AP-1). Results of in vitro kinase assays showed that exogenously added PBN completely blocked the c-Jun phosphorylating activity of JNK. Interestingly, using in vitro kinase assay, we also found that chondrocyte p38-MAPK phosphorylate c-Jun and that PBN was not very effective in inhibiting c-Jun phosphorylating activity of p38-MAPK. In addition, PBN did not block the ATF-2 phosphorylating activity of p38-MAPK and Elk-1 phosphorylating activity of extracellular regulated kinase p44/p42 in vitro, indicating that PBN may act selectively to inhibit the phosphorylation of c-Jun in OA chondrocytes. Together, our results for the first time demonstrate that PBN suppresses the IL-1β-stimulated expression of MMP-13 in OA chondrocytes and that this was achieved by inhibiting the activation of JNK and AP-1. These results suggest that use of PBN or compounds derived from it may be of potential benefit in inhibiting signaling events associated with cartilage degradation in arthritis. The American Society for Pharmacology and Experimental Therapeutics ER -