Suppression of adjuvant-induced arthritic bone destruction by cyclooxygenase-2 selective agents with and without inhibitory potency against carbonic anhydrase II
Suppression of adjuvant-induced arthritic bone destruction by cyclooxygenase-2 selective agents with and without inhibitory potency against carbonic anhydrase II
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DOI：
10.1359/jbmr.051025
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发表时间：
2006-02-01
影响因子：
6.2
通讯作者：
Kawaguchi, H
中科院分区：
文献类型：
--
作者：
Katagiri, M;Ogasawara, T;Kawaguchi, H
简介：已知环加氧酶（COX）-2和碳酸酐酶II（CA II）分别在破骨细胞的分化和成熟破骨细胞的活性中发挥重要作用。由于最近发现几种COX-2选择性药物对CA II具有抑制效力，因此本研究比较了具有和不具有CA II抑制效力的COX-2选择性药物的骨保留效果。 材料和方法：通过小鼠成骨细胞和骨髓细胞共培养系统测定破骨细胞分化，并通过由骨髓细胞产生和分离的破骨细胞吸收的牙本质切片上的凹坑面积来测量成熟破骨细胞的活性。通过对佐剂诱发关节炎 (AIA) 大鼠的后爪进行放射学和组织学分析，确定对关节炎骨质破坏的体内影响。结果：CA II 主要在成熟破骨细胞中表达，但在前体细胞中不表达。与 CA II 抑制剂乙酰唑胺相似，磺酰胺型 COX-2 选择性药物塞来昔布和 JTE-522 也可抑制 CA II 活性，但甲砜型 COX-2 抑制剂罗非考昔不会抑制 CA II 活性。体外试验清楚地表明，塞来考昔和 JTE-522 抑制破骨细胞的分化和活性，而罗非考昔和乙酰唑胺分别仅抑制破骨细胞的分化和激活。然而，所有 COX-2 选择性药物（无论是否具有 CA II 抑制效力）均能有效且类似地抑制 AIA 大鼠的骨破坏，尽管乙酰唑胺的抑制作用仅为中度。结论：对于治疗关节炎骨破坏，通过抑制 COX-2 抑制破骨细胞分化比通过抑制 CA II 抑制成熟破骨细胞活性更有效。
Introduction: Cyclooxygenase (COX)-2 and carbonic anhydrase II (CA II) are known to play important roles in the differentiation of osteoclasts and the activity of mature osteoclasts, respectively. Because several COX-2 selective agents were recently found to possess an inhibitory potency against CA II, this study compared the bone sparing effects of COX-2 selective agents with and without the CA II inhibitory potency.Materials and Methods: Osteoclast differentiation was determined by the mouse co-culture system of osteoblasts and bone marrow cells, and mature osteoclast activity was measured by the pit area on a dentine slice resorbed by osteoclasts generated and isolated from bone marrow cells. In vivo effects on arthritic bone destruction were determined by radiological and histological analyses of hind-paws of adjuvant-induced arthritic (AIA) rats.Results: CA II was expressed predominantly in mature osteoclasts, but not in the precursors. CA II activity was inhibited by sulfonamide-type COX-2 selective agents celecoxib and JTE-522 similarly to a CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib. In vitro assays clearly revealed that celecoxib and JTE-522 suppressed both differentiation and activity of osteoclasts, whereas rofecoxib and acetazolamide suppressed only osteoclast differentiation and activation, respectively. However, bone destruction in AIA rats was potently and similarly suppressed by all COX-2 selective agents whether with or without CA II inhibitory potency, although only moderately by acetazolamide.Conclusions: Suppression of osteoclast differentiation by COX-2 inhibition is more effective than suppression of mature osteoclast activity by CA II inhibition for the treatment of arthritic bone destruction.