Selective cyclooxygenase-2 inhibitor prevents reduction of trabecular bone mass in collagen-induced arthritic mice in association with suppression of RANKL/OPG ratio and IL-6 mRNA expression in synovial tissues but not in bone marrow cells
Selective cyclooxygenase-2 inhibitor prevents reduction of trabecular bone mass in collagen-induced arthritic mice in association with suppression of RANKL/OPG ratio and IL-6 mRNA expression in synovial tissues but not in bone marrow cells
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DOI：
10.1007/s00774-007-0808-2
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Nakamura, Toshitaka
中科院分区：
文献类型：
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作者：
Taketa, Tomonori;Sakai, Akinori;Nakamura, Toshitaka
本研究旨在阐明塞来昔布（一种选择性环氧合酶-2（考克斯-2）抑制剂）是否通过抑制关节炎相关的骨吸收增加来预防骨小梁骨量减少，并区分塞来昔布、SC-58560（一种选择性考克斯-1抑制剂）和吲哚美辛对骨作用的差异。将8周龄的DBA/1 J雄性小鼠分成如下6组。将对照未处理（正常）和胶原诱导的关节炎（CIA）小鼠与四个处理组进行比较：除了用SC-58560（COX 1）或吲哚美辛（IND）处理的两组小鼠外，CIA小鼠还经口给予剂量为0（溶媒）、16（COX 2L）和75（COX 2 H）mg/kg的塞来昔布。组织形态计量学显示关节炎小鼠胫骨骨小梁体积显著减少，COX 2 H可纠正该现象。COX 2L、COX 2 H和IND抑制了溶媒组中破骨细胞表面和数量的增加。COX 2 H升高了溶媒组中骨形成率的降低，但无统计学意义。COX 2 L和COX 2 H可抑制溶媒滑膜组织中NF-κ B配体受体激活因子（RANKL）/骨保护素（OPG）的高比例mRNA表达。溶剂中白细胞介素（IL）-6 mRNA表达的增加被COX 2L、COX 2 H和IND抑制，尽管在所有组中骨髓细胞中未观察到该表达的差异。总之，在CIA小鼠中，塞来昔布在低剂量和高剂量下抑制关节炎相关的骨吸收增加，并在高剂量下通过抑制炎症性滑膜组织中RANKL/OPG比值和IL-6 mRNA表达来防止骨小梁骨量减少，并抑制骨髓中破骨细胞的发育。
We performed this study to clarify whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, prevents trabecular bone mass reduction by suppressing arthritis-related increase of bone resorption, and to discriminate differences in actions on bone among celecoxib, SC-58560 (a selective COX-1 inhibitor), and indomethacin. Eight-week-old DBA/1J male mice were divided into six groups as follows. Control untreated (Normal) and collagen-induced arthritic (CIA) mice were compared with four treatment groups: celecoxib was orally administered to CIA mice at doses of 0 (Vehicle), 16 (COX2L), and 75 (COX2H) mg/kg, in addition to two groups of mice treated with SC-58560 (COX1) or indomethacin (IND). Histomorphometry showed a significant decrease in tibial trabecular bone volume in arthritic mice, which was corrected by COX2H. The increased osteoclast surface and number in the Vehicle group were suppressed by COX2L, COX2H, and IND. The decreased bone formation rate in Vehicle was elevated by COX2H without statistical significance. A high ratio of mRNA expression of receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) in Vehicle synovial tissue was suppressed by COX2L and COX2H. The increased expression of interleukin (IL)-6 mRNA in Vehicle was suppressed by COX2L, COX2H, and IND, although no difference in this expression was observed in bone marrow cells among all groups. In conclusion, in CIA mice, celecoxib suppresses arthritis-related increase in bone resorption at low and high doses and prevents trabecular bone mass reduction at high doses in association with suppression of osteoclast development in bone marrow through inhibition of RANKL/OPG ratio and IL-6 mRNA expression in inflammatory synovial tissue.