雷洛昔芬对骨保护蛋白基因缺失小鼠的抗骨质疏松作用  

Anti-osteoporotic effect of raloxifene on mice with osteoprotegerin gene deficiency

作　　者：颜美珠[1] 庞小芬[1] 许勇[2] 李西华[3] 孔辉[3] 陆顺元[3] 巩云霞[1] 王萍[1] 赵咏桔[1] 

机构地区：[1]上海交通大学附属瑞金医院老年科,200025 [2]上海交通大学附属瑞金医院伤科,200025 [3]上海交通大学医学院遗传教研室

出　　处：《中华内分泌代谢杂志》2008年第4期372-376,共5页Chinese Journal of Endocrinology and Metabolism

基　　金：上海市科委基础研究项目（05JC14034）

摘　　要：目的利用骨保护蛋白（osteoprotegerin，OPG）基因剔除小鼠模型研究选择性雌激素受体调节剂雷洛昔芬对雌鼠和雄鼠的抗骨质疏松作用。方法取二月龄OPG基因剔除（OPG^-/-）的雌鼠和雄鼠各20只。随机分为雷洛昔芬组（3mg·kg^-1·d^-1）和安慰剂组，另取野生型雌鼠10只作为对照组，1个月后杀鼠取材。测量骨密度、骨生物力学、骨形态计量学，并进行骨组织病理学检查及破骨细胞染色，评价雷洛昔芬的疗效。结果OPG^-/-小鼠呈现明显的骨质疏松表型。雷洛昔芬组的雌鼠较安慰剂组腰椎、股骨骨密度明显增高（均P〈0．05）；骨生物力学结果显示腰椎和股骨最大载荷（P〈0.05或P〈0．01），弹性模量（P〈0．05或P〈0．01），结构韧性（均P〈0．01）均增高，提示骨折风险性下降；破骨细胞染色示腰椎和股骨破骨细胞面积明显减少（均P〈0．01）；HE染色示骨小梁数目增加，连接性上升；骨形态计量学结果显示骨形成率降低（P〈0．05）。雷洛昔芬组的雄鼠与安慰剂组相比较无上述改变。结论选择性雌激素受体调节剂雷洛昔芬在OPG基因缺失的情况下仍可改善雌鼠骨质疏松，其作用不完全依赖于OPG基因。雷洛昔芬对OPG^-/-雄鼠无效。Objective To observe the effect of raloxifene, a selective estrogen receptor modulator, on osteoporosis in the osteoprotegerin （OPG） gene knock-out female and male mice. Methods Two groups of OPG gene deficient （OPG^-/- ） female and male mice, 20 mice in each group, were assigned to raloxifene-treated （3 mg · kg^-1·d^-1） group and placebo group randomly. Ten female mice with wild-gene type were served as control. The effect of raloxifene was evaluated by comparing the values of bone mineral density （BMD） , bone strength, histomorphometric measurement and osteoclast number between the raloxifene treated group and placebo group. Results As compared with placebo group osteoporotic manifestations were improved in OPG^-/- female mice treated with raloxifene orally. BMD was increased both in lumbar vertebrae （ P 〈 0.05 ） and femurs （ P 〈 0.01 ）. Bone strength was measured in femurs by three-point bending test and vertebrae by stress test. Results showed that ultimate load, ultimate stress and Young＇s modulus were increased both at lumbar and femur bone, suggesting decreased risk of fracture. Tartrate-resistant acid phosphatase, a marker enzyme of osteoclasts, was detected, and the number of osteoclasts declined significantly after the treatment of raloxifene. At the same time, results of histomorphometric measurements indicated that bone trabecular volume was increased and bone formation rate decreased from （ 8.05 ±4.02） mm^3 · mm^-2 . year^-1 to （ 5.48 ± 1.89 ） mm3·mm^-2· year^-1 （ P 〈 0.05 ）. These findings were found in the group of OPG^-/- female mice treated with reloxifene but not in male mice. Conclusions Raloxifene is effective in treating osteoporosis in female OPG^-/- mice, indicating that its action is at least in part independent of OPG gene. But it is ineffective in male OPG^-/- mice.

关 键 词：选择性雌激素受体调节剂 骨保护素 骨质疏松 

分 类 号：R580[医药卫生—内分泌]