4'-Hydroxy aceclofenac suppresses the interleukin-1-induced production of promatrix metalloproteinases and release of sulfated-glycosaminoglycans from rabbit articular chondrocytes.
This study demonstrates the novel actions of a non-steroidal anti-inflammatory drug aceclofenac, which is frequently used for rheumatoid arthritis and osteoarthritis. 4'-Hydroxy aceclofenac, a main metabolite of aceclofenac in humans, down-regulated the production of promatrix metalloproteinase-1/procollagenase 1 and promatrix metalloproteinase-3/prostromelysin 1 along with a decrease in their mRNAs in rabbit articular chondrocytes and synoviocytes, and interfered with the release of sulfated-glycosaminoglycans (proteoglycans) from the chondrocytes. 4'-Hydroxy aceclofenac also suppressed the proliferation of rabbit synoviocytes. In contrast, aceclofenac itself and its other metabolites, diclofenac and 4'-hydroxy declofenac, did not exert obvious actions on cellular functions. Therefore, it is suggested that the therapeutic effects of aceclofenac on rheumatoid arthritis and osteoarthrits are, at least in part, due to the novel chondroprotective effect of 4'-hydroxy aceclofenac via the suppression of promatrix metalloproteinase production and proteoglycan release. There is also evidence that inhibition of synoviocyte proliferation and the known inhibitory action on prostaglandin E(2) production play a role.
Akimoto
H
H
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, 192-0392, Tokyo, Japan.
Yamazaki
R
R
Hashimoto
S
S
Sato
T
T
Ito
A
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002358:Cartilage, Articular / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004008:Diclofenac / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006025:Glycosaminoglycans / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D013583:Synovial Membrane / Q000166:cytology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004792:Enzyme Precursors; D006025:Glycosaminoglycans; D007375:Interleukin-1; D012333:RNA, Messenger; D004008:Diclofenac; D020782:Matrix Metalloproteinases