Akimoto H, Yamazaki R, Hashimoto S, Sato T, Ito A
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, 192-0392, Tokyo, Japan.
Eur J Pharmacol. 2000 Aug 11;401(3):429-36. doi: 10.1016/s0014-2999(00)00472-6.
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.
本研究证实了非甾体抗炎药醋氯芬酸的新作用，该药常用于治疗类风湿性关节炎和骨关节炎。4'-羟基醋氯芬酸是醋氯芬酸在人体内的主要代谢产物，它可下调兔关节软骨细胞和滑膜细胞中前基质金属蛋白酶-1/原胶原酶1和前基质金属蛋白酶-3/前基质溶素1的产生，并使其mRNA水平降低，同时还能抑制软骨细胞中硫酸化糖胺聚糖（蛋白聚糖）的释放。4'-羟基醋氯芬酸还可抑制兔滑膜细胞的增殖。相比之下，醋氯芬酸本身及其其他代谢产物双氯芬酸和4'-羟基双氯芬酸对细胞功能无明显作用。因此，提示醋氯芬酸对类风湿性关节炎和骨关节炎的治疗作用至少部分归因于4'-羟基醋氯芬酸通过抑制前基质金属蛋白酶产生和蛋白聚糖释放而具有的新的软骨保护作用。也有证据表明抑制滑膜细胞增殖以及对前列腺素E(2)产生的已知抑制作用也发挥了作用。
