Noguchi Masahiro, Kimoto Aishi, Sasamata Masao, Miyata Keiji
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan.
J Bone Miner Metab. 2008;26(5):461-8. doi: 10.1007/s00774-008-0855-3. Epub 2008 Aug 30.
Cyclooxygenase (COX)-2 is known to play an important role in the differentiation and maturation of osteoclasts. However, the role of COX-1 in bone metabolism has not been well explored. In this study, the bone-conserving effects of COX-2-specific (celecoxib), COX-nonselective (loxoprofen), and COX-1-specific agents (SC-58560) were compared using an adjuvant-induced arthritis (AIA) rat model. Arthritis was induced by injecting 50 microl liquid paraffin containing 1 mg Mycobacterium butyricum into the left footpad of Lewis rats. Drugs were given orally twice daily for 10 days beginning 15 days after adjuvant injection. Celecoxib was administered at the rate of 3 mg/kg per day, loxoprofen at 3 mg/kg per day, and SC-58560 at 10 mg/kg per day. The therapeutic effects on 3-D architectural bone changes in the arthritic condition, e.g., the bone volume/total tissue volume ratio and the amount of trabecular bone pattern factor, were determined by analyzing the hindpaw calcaneus of AIA rats using microcomputed tomography (micro-CT). In addition, dual-energy X-ray absorptiometry 2-D bone analysis was performed to compare with micro-CT analysis. AIA rats are prone to substantial bone erosion, which allows for significant changes in the 3-D architectural index. This inflammatory bone destruction was suppressed potently by celecoxib, only moderately by loxoprofen, and not at all by SC-58560. These data suggest that COX-2 plays an important role in the inflammatory bone destruction that occurs with rheumatoid arthritis. The results also suggest that COX-2 is more effective than COX-1 at suppressing the destruction of bone associated with arthritis.
已知环氧化酶（COX）-2在破骨细胞的分化和成熟过程中发挥重要作用。然而，COX-1在骨代谢中的作用尚未得到充分研究。在本研究中，使用佐剂诱导的关节炎（AIA）大鼠模型比较了COX-2特异性药物（塞来昔布）、COX非选择性药物（洛索洛芬）和COX-1特异性药物（SC-58560）的保骨作用。通过将含有1mg丁酸分枝杆菌的50微升液体石蜡注射到Lewis大鼠的左足垫来诱导关节炎。在佐剂注射15天后开始，每天口服给药两次，持续10天。塞来昔布的给药剂量为每天3mg/kg，洛索洛芬为每天3mg/kg，SC-58560为每天10mg/kg。通过使用微型计算机断层扫描（micro-CT）分析AIA大鼠的后爪跟骨，确定对关节炎状态下三维骨结构变化的治疗效果，例如骨体积/总组织体积比和小梁骨模式因子的量。此外，进行双能X线吸收法二维骨分析以与micro-CT分析进行比较。AIA大鼠容易发生大量骨侵蚀，这使得三维结构指数发生显著变化。这种炎性骨破坏被塞来昔布强烈抑制，被洛索洛芬中度抑制，而SC-58560则完全没有抑制作用。这些数据表明COX-2在类风湿性关节炎发生的炎性骨破坏中起重要作用。结果还表明，在抑制与关节炎相关的骨破坏方面，COX-2比COX-1更有效。
