A major metabolite of aceclofenac, 4'-hydroxy aceclofenac, suppresses the production of interstitial pro-collagenase/proMMP-1 and pro-stromelysin-1/proMMP-3 by human rheumatoid synovial cells.
OBJECTIVE
We examined the effects of aceclofenac and its metabolites on the production of pro-collagenase-1/pro-matrix metalloproteinase-1 (proMMP-1), pro-gelatinase A/proMMP-2, pro-stromelysin-1/proMMP-3 and tissue inhibitor of metalloproteinases-1 (TIMP-1) by rheumatoid synovial cells.


METHODS
Synovial cells were obtained from patients with rheumatoid arthritis.


METHODS
Cultures of confluent cells were treated with interleukin-1beta (IL-1beta)(1 ng/ml) and/or test drugs (0.3-30 microM) for 48 h.


METHODS
Production of proMMPs and TIMP-1 was monitored by Western blotting or gelatin zymography. Prostaglandin E2 (PGE2) was measured by an enzyme immunoassay.


RESULTS
4'-Hydroxy aceclofenac, a major metabolite of aceclofenac, down-regulated both basal and IL-1beta-induced production of proMMP-1 and proMMP-3 at a concentration sufficient to suppress PGE2 production without modulating proMMP-2 or TIMP-1, whereas aceclofenac itself had no marked effect on the production of proMMPs.


CONCLUSIONS
Down-regulation of proMMP-1 and proMMP-3 production by 4'-hydroxy aceclofenac may contribute to the therapeutic effect of aceclofenac on rheumatoid arthritis and osteoarthritis.
Yamazaki
R
R
Yakult Central Institute for Microbiological Research, Tokyo, Japan. ryuta-yamazaki@yakult.co.jp
Kawai
S
S
Mizushima
Y
Y
Matsuzaki
T
T
Hashimoto
S
S
Yokokura
T
T
Ito
A
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors*; D005110:Extracellular Space / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
C108035:4'-hydroxyaceclofenac; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004792:Enzyme Precursors; D007375:Interleukin-1; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D004008:Diclofenac; D008666:Metalloendopeptidases; C048047:prostromelysin; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone; C056498:aceclofenac