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Regulation of metalloproteinases and NF‐ κ B activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA
Author(s) -
Pillinger Michael H,
Dinsell Victoria,
Apsel Beth,
Tolani Sonia N,
Marjanovic Nada,
Chan Edwin S L,
Gomez Paul,
Clancy Robert,
Chang LihFan,
Abramson Steven B
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705864
Subject(s) - nabumetone , mapk/erk pathway , chemistry , prostaglandin e2 , matrix metalloproteinase , secretion , proinflammatory cytokine , prostaglandin e , prostaglandin , inflammation , pharmacology , medicine , microbiology and biotechnology , biochemistry , biology , signal transduction , nonsteroidal
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). Brief exposures to 6MNA (50–150 μ M ) had no effect on IL‐1 β /TNF‐ α (each 20 ng ml −1 )‐stimulated Erk activation. Longer exposures depleted prostaglandin E 1 (PGE 1 ) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 μ M ) inhibited Erk activation by 60–80%. 6MNA (50–150 μ M ) stimulated (∼200%) and nabumetone (150 μ M ) inhibited (∼50%) matrix metalloproteinase (MMP)‐1, but not MMP‐13 secretion from SFs. 6MNA stimulation of MMP‐1 secretion was inhibited ∼30% by PGE 1 (1 μ M ) and ∼80% by the Erk pathway inhibitor UO126 (10 μ M ), confirming that PGE depletion and Erk activation mediate MMP‐1 secretion by 6MNA. Consistent with its role as an Erk inhibitor, nabumetone (150 μ M ) abrogated 6MNA enhancement of MMP‐1 secretion. UO126 (10 μ M ) and nabumetone (150 μ M ) inhibited (∼70 and 40%, respectively), but 6MNA (150 μ M ) enhanced (∼40%), NF‐ κ B activation. 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.British Journal of Pharmacology (2004) 142 , 973–982. doi: 10.1038/sj.bjp.0705864