Abstract

A new therapeutic option to treat osteoporosis is focused on Wnt signaling and its inhibitor sclerostin, a product of the Sost gene. In this work, we study the effect of sclerostin deficiency on trabecular bone formation and resorption in male and female mice and whether it affects mechano-responsiveness. Male and female 10- and 26-week-old Sost knockout (KO) and littermate controls (LCs) were subjected to in vivo mechanical loading of the left tibia for 2 weeks. The right tibia served as internal control. The mice were imaged using in vivo micro-computed tomography at days 0, 5, 10, and 15 and tibiae were collected for histomorphometric analyses after euthanasia. Histomorphometry and micro-CT-based 3D time-lapse morphometry revealed an anabolic and anti-catabolic effect of Sost deficiency although increased trabecular bone resorption accompanied by diminished trabecular bone formation occurred with age. Loading led to diminished resorption in adult female but not in male mice. A net gain in bone volume could be achieved with mechanical loading in Sost KO adult female mice, which occurred through a further reduction in resorbed bone volume. Our data show that sclerostin deficiency has a particularly positive effect in adult female mice. Sclerostin antibodies are approved to treat postmenopausal women with high risk of osteoporotic fractures. Further studies are required to clarify whether both sexes benefit equally from sclerostin inhibition.

中文翻译：

---

长期硬化素缺乏对雄性和雌性小鼠小梁骨质量和对肢体负荷适应的影响。

摘要

一种治疗骨质疏松症的新治疗选择集中在Wnt信号及其抑制剂硬化蛋白（Sost基因的产物）上。在这项工作中，我们研究了硬化素缺乏对雄性和雌性小鼠小梁骨形成和吸收的影响，以及它是否影响机械反应性。分别对10周和26周的男性和女性Sost基因敲除（KO）和同窝仔对照（LCs）进行体内左胫骨机械负荷2周。右胫骨作为内部控制。在第0、5、10和15天使用体内微型计算机断层扫描对小鼠成像，并在安乐死后收集胫骨进行组织形态分析。组织形态计量学和基于微CT的3D延时形态计量学显示了Ab的合成代谢和抗分解代谢作用SOST不足虽然伴随着减少骨小梁形成增加小梁骨吸收发生与年龄无关。负荷导致成年雌性的吸收减少，但雄性小鼠却没有。Sost KO成年雌性小鼠的机械负荷可以实现骨量的净增加，这是通过进一步减少吸收的骨量实现的。我们的数据表明，硬化素缺乏症在成年雌性小鼠中具有特别积极的作用。已批准硬化蛋白抗体治疗患有骨质疏松性骨折高风险的绝经后妇女。需要进一步的研究来阐明两性是否都从硬化蛋白抑制中同样受益。