Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength
Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength
复制标题
DOI：
10.1359/jbmr.080216
复制
发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Paszty, Chris
中科院分区：
文献类型：
--
作者：
Li, Xiaodong;Ominsky, Michael S.;Paszty, Chris
简介：硬化症是一种罕见的人类高骨量遗传性疾病，由编码硬化素的基因 SOST 失活突变引起。根据这些数据，硬化蛋白已成为骨量的关键负调节剂。我们生成了 SOST 敲除 (KO) 小鼠，以更详细地了解硬化素缺乏对骨骼的影响。材料和方法：使用基因打靶来灭活 SOST，并生成一系列 SOST KO 小鼠。使用射线照相、密度测定、μ CT、组织形态测定和机械测试来表征硬化素缺乏对雄性和雌性小鼠骨的影响。在同性 KO 和野生型 (WT) 小鼠之间进行比较。结果：雄性和雌性 SOST KO 小鼠的结果相似，仅在某些影响的程度方面存在差异。 SOST KO 小鼠整个骨骼的放射密度增加，总体骨骼形态外观正常。腰椎和整条腿的 DXA 分析显示，两个部位的 BMD 均显着增加（>50%）。股骨的 mu CT 分析表明，小梁和皮质区的骨量均显着增加。骨小梁的组织形态计量学显示，SOST KO 小鼠中成骨细胞表面显着增加，而破骨细胞表面没有显着变化。 SOST KO 小鼠股骨远端的骨小梁（> 9 倍）以及股骨中轴的皮质内和骨膜表面的骨形成率显着增加。腰椎和股骨的力学测试显示，SOST KO 小鼠两个部位的骨强度均显着增加。结论：SOST KO 小鼠具有高骨量表型，其特征是 BMD、骨体积、骨形成和骨强度显着增加。这些结果表明，硬化蛋白是强大的、进化上保守的骨形成途径的关键负调节因子，该途径作用于小梁骨和皮质骨。
Introduction: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone.Materials and Methods: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, mu CT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice.Results: The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. mu CT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice.Conclusions: SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone.