Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice
Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice
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DOI：
10.1002/art.33324
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发表时间：
2012-01-01
影响因子：
--
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
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作者：
Fukai, Atsushi;Kamekura, Satoru;Kawaguchi, Hiroshi
目的探讨环氧化酶2（考克斯-2）抑制剂对实验性骨关节炎（OA）软骨的保护作用。方法.通过对手术诱导的膝关节不稳定小鼠和接受全膝关节置换术的OA患者的胫骨软骨进行免疫染色，检测前列腺素E（2）合成酶的表达。在诱导OA后12周，检查了塞来昔布（10 mg/ kg/天和30 mg/ kg/天）或溶剂单独经口给药对小鼠的影响。为了研究考克斯-1和考克斯-2在OA发展中的参与，我们还在考克斯-1-同源基因敲除（Ptgs 1-/-）小鼠和考克斯-2-同源基因敲除（Ptgs 2-/-）小鼠中建立了模型。OA的严重程度采用我们小组开发的分级系统和骨关节炎研究学会国际评分系统进行评估。结果在小鼠和人OA软骨中，诱导酶考克斯-2和微粒体前列腺素E合酶1（mPGES-1）的表达增强，而组成酶考克斯-1、胞质PGES和mPGES-2的表达受到抑制。在小鼠模型中，每日塞来昔布治疗不能防止OA发展期间的软骨降解或骨赘形成。此外，与野生型同窝仔相比，Ptgs 1-/-小鼠和Ptgs 2-/-小鼠在OA发展方面均未表现出任何显著差异。结论这两种考克斯酶在OA发展过程中的表达调节方面不同。然而，使用抑制剂和遗传缺陷的实验证明在小鼠手术OA模型中考克斯-2抑制缺乏软骨保护作用。
Objective To investigate the chondroprotective effect of cyclooxygenase 2 (COX-2) inhibition in experimental osteoarthritis (OA). Methods. The expression of prostaglandin E(2) synthetic enzymes was examined by immunostaining of tibial cartilage from mice with surgically induced knee joint instability and from OA patients undergoing total knee arthroplasty. The effect of orally administered celecoxib (10 mg/ kg/ day and 30 mg/ kg/ day) or vehicle alone in mice was examined 12 weeks after the induction of OA. To investigate the involvement of COX-1 and COX-2 in OA development, we also created the model in COX-1-homozygous-knockout (Ptgs1-/-) mice and COX-2-homozygous-knockout (Ptgs2-/-) mice. OA severity was assessed using a grading system developed by our group and by the Osteoarthritis Research Society International scoring system. Results. In mouse and human OA cartilage, the expression of the inducible enzymes COX-2 and microsomal prostaglandin E synthase 1 (mPGES-1) was enhanced, while that of the constitutive enzymes COX-1, cytosolic PGES, and mPGES-2 was suppressed. Daily celecoxib treatment did not prevent cartilage degradation or osteophyte formation during OA development in the mouse model. Furthermore, neither Ptgs1-/- mice nor Ptgs2-/- mice exhibited any significant difference in OA development as compared to wild-type littermates. Conclusion. The two COX enzymes differ in terms of regulation of their expression during OA development. Nevertheless, experiments using inhibitor and genetic deficiency demonstrated a lack of chondroprotective effect of COX-2 inhibition in the mouse surgical OA model.