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.
Pillinger
Michael H
MH
The Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. michael.pillinger@med.nyu.edu
Dinsell
Victoria
V
Apsel
Beth
B
Tolani
Sonia N
SN
Marjanovic
Nada
N
Chan
Edwin S L
ES
Gomez
Paul
P
Clancy
Robert
R
Chang
Lih-Fan
LF
Abramson
Steven B
SB
D000527:Alprostadil / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002074:Butanones / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000077430:Nabumetone; D009280:Naphthaleneacetic Acids / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011458:Prostaglandins E / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002070:Butadienes; D002074:Butanones; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D016328:NF-kappa B; D009280:Naphthaleneacetic Acids; D009570:Nitriles; D011458:Prostaglandins E; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D009569:Nitric Oxide; C044612:6-methoxy-2-naphthylacetic acid; D015237:Dinoprost; D048049:Extracellular Signal-Regulated MAP Kinases; D008666:Metalloendopeptidases; D020781:Matrix Metalloproteinase 1; D000527:Alprostadil; D000077430:Nabumetone; C093642:SB 203580