Increased callus mass and enhanced strength during fracture healing in mice lacking the sclerostin gene
Increased callus mass and enhanced strength during fracture healing in mice lacking the sclerostin gene
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DOI：
10.1016/j.bone.2011.08.012
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发表时间：
2011-12-01
期刊：
影响因子：
4.1
通讯作者：
Ke, Hua Zhu
中科院分区：
文献类型：
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作者：
Li, Chaoyang;Ominsky, Michael S.;Ke, Hua Zhu
患有遗传性硬化素缺乏症的人骨量较高。小鼠硬化素基因的定向缺失（SOST-KO）会导致骨形成、骨量和骨强度增加。在啮齿动物和灵长类动物模型中，单克隆抗体对硬化蛋白的抑制可增加骨形成并增强骨折愈合。在这项研究中，我们描述了与野生型（WT）对照小鼠相比，SOST-KO 小鼠股骨骨折愈合的时间进展，以进一步表征硬化素在骨折愈合中的作用。 67 只 9-10 周龄雄性 SOST-KO (N = 37) 和 'NT (N = 30) 小鼠经历了闭合性股骨骨折。每周进行放射线照相来监测愈合进度。在第 14 天和第 28 天，使用组织学切片来表征愈伤组织成分、评估愈伤组织桥接并量化板层骨形成。使用密度测定和生物力学测试来表征第 45 天骨折股骨和对侧股骨的骨量和强度。 14 天（WT 为 38%，WT 为 0%）。骨折后 28 天，两种基因型似乎几乎完全桥接。与 WT 小鼠相比，第 14 天时桥接的增加与 SOST-KO 小鼠愈伤组织中骨面积增加 97% 和软骨面积减少 40% 相关。 SOST-KO 小鼠在第 14 天和第 28 天的骨形成相关终点均较高。骨折后 45 天，与 WT 小鼠相比，SOST-KO 小鼠骨折股骨的峰值负荷和骨量显着更高。 总之，缺乏硬化素的小鼠骨折显示出桥接加速、骨痂成熟程度更高、骨形成和骨痂强度增加。 (C) 2011 Elsevier Inc. 保留所有权利。
Humans with inherited sclerostin deficiency have high bone mass. Targeted deletion of the sclerostin gene in mice (SOST-KO) causes increases in bone formation, bone mass and bone strength. Inhibition of sclerostin by a monoclonal antibody increases bone formation and enhances fracture healing in rodent and primate models. In this study, we describe the temporal progression of femoral fracture healing in SOST-KO mice compared with wild type (WT) control mice to further characterize the role of sclerostin in fracture healing. Sixty-seven male 9-10 week-old SOST-KO (N = 37) and 'NT (N = 30) mice underwent a closed femoral fracture. Weekly radiography was used to monitor the progress of healing. Histologic sections were used to characterize callus composition, evaluate callus bridging, and quantify lamellar bone formation on days 14 and 28. Densitometry and biomechanical testing were utilized to characterize bone mass and strength at the fractured and contralateral femurs on day 45.A significant improvement in time to radiographic healing (no discernible fracture line) was observed in SOST-KO mice, which corresponded to an increase in histologic bony bridging at 14 days (38% versus 0% in WT). Both genotypes appeared to be nearly fully bridged at 28 days post-fracture. The increased bridging at 14 days was associated with 97% greater bone area and 40% lower cartilage area in the callus of SOST-KO mice as compared to WT mice. Bone formation-related endpoints were higher in SOST-KO mice at both 14 and 28 days. At 45 days post-fracture, peak load and bone mass were significantly greater in the fractured femurs of SOST-KO mice as compared to WT mice.In conclusion, fractures in mice lacking sclerostin showed accelerated bridging, greater callus maturation, and increased bone formation and strength in the callus. (C) 2011 Elsevier Inc. All rights reserved.