15-Deoxy-Δ12,14-Prostaglandin-J2 and Ciglitazone Inhibit TNF-α-Induced Matrix Metalloproteinase 13 Production Via the Antagonism of NF-κB Activation in Human Synovial Fibroblasts

Collagenase-3 (matrix metalloproteinase, MMP-13) plays an important role in the degradation of cartilage in pathologic conditions. MMP-13 is elevated in joint tissues in both rheumatoid arthritis (RA) and osteoarthritis (OA). In addition, inflammation-stimulated synovial fibroblasts are able to release MMP-13 and other cytokines in these diseases. The peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands are recently considered as new anti-inflammatory compounds and these ligands were reported to ameliorate inflammatory arthritis. The aim of this study is to evaluate the mechanisms how PPAR gamma ligands inhibit the inflammatory response in synovial fibroblasts. Two PPAR gamma ligands, cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin-J2 (15d-PGJ2) and synthetic thiazolidinedione compound ciglitazone were examined in this study. Here we found that 15d-PGJ2 and ciglitazone markedly inhibited TNF-alpha-induced MMP-13 production in human synovial fibroblasts. In addition, activation of nuclear factor kappa B (NF-kappa B) is strongly associated with MMP-13 induction by TNF-alpha and the activation of NF-kappa B was determined by Western blot, reporter assay, and immunofluorescence. It was found that 15d-PGJ2 markedly attenuated the translocation of NF-kappa B by direct inhibition of the activation of IKK via a PPAR gamma-independent manner. Ciglitazone also inhibits TNF-alpha-induced MMP-13 expression by suppressing NF-kappa B activation mainly via the modulation of p38-MAPK. Collectively, our data demonstrate that 15d-PGJ2 and ciglitazone attenuated TNF-alpha-induced MMP-13 expression in synovial fibroblasts primarily through the modulation of NF-kappa B signaling pathways. These compounds may have therapeutic application in inflammatory arthritis. J. Cell. Physiol. 226: 3242-3250, 2011. (C) 2011 Wiley Periodicals, Inc.