Regulation of metalloproteinases and NF-kappaB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA.

1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated.

Cyclooxygenase-2-derived E prostaglandins down-regulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via inhibition of extracellular signal-regulated kinase activation.

We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1beta and TNF-alpha stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE(1) or PGE(2) inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC.