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.
Pillinger
Michael H
MH
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. michael.pillinger@med.nyu.edu
Rosenthal
Pamela B
PB
Tolani
Sonia N
SN
Apsel
Beth
B
Dinsell
Victoria
V
Greenberg
Jeffrey
J
Chan
Edwin S L
ES
Gomez
Paul F
PF
Abramson
Steven B
SB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015536:Down-Regulation / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011458:Prostaglandins E / Q000502:physiology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D011458:Prostaglandins E; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D001241:Aspirin