Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice.
Sostdc1 Suppression in the Absence of Sclerostin Potentiates Anabolic Action of Cortical Bone in Mice.
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在缺乏硬化素的情况下抑制 Sostdc1 可增强小鼠皮质骨的合成代谢作用。
DOI：
10.1002/jbmr.4798
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Robling,AlexanderG
中科院分区：
文献类型：
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作者：
Choi,RoyB;Hoggatt,AprilM;Horan,DanielJ;Rogers,EmilyZ;Loots,GabrielaG;Robling,AlexanderG
近年来，基于Wnt的骨合成代谢药物的开发进展迅速，因为Wnt对骨稳态有很强的调节作用。同时对Wnt拮抗剂skerostin和Dkk1的药物抑制可以优化，以在松质骨间产生增强效应。我们寻找可能与硬化素共同抑制的其他候选药物，以增强皮质隔室的影响。Sostdc1(Wise)，像硬化素和Dkk1一样，也结合和抑制LRP5/6辅助受体以削弱规范的Wnt信号，但Sostdc1在皮质骨中的作用更大。为了测试这一概念，我们从小鼠身上删除了Sostdc1和SOST，并分别测量了皮质和松质骨间隔中的骨骼效应。Sost缺失单独会在所有椎间产生高骨量，而Sostdc1缺失单独对两个包膜都没有可测量的影响。Sostdc1和SOST共缺失的小鼠具有较高的骨量和增加的皮质特性(骨量、形成率、机械特性)，但仅限于雄性。在野生型雌性小鼠中联合应用硬化素抗体和Sostdc1抗体可增强皮质骨的增长，而单独使用Sostdc1抗体则不起作用。总之，Sostdc1抑制/缺失可以与硬化素缺乏症协同作用，改善皮质骨的特性。作者：《骨与矿物研究杂志》，由Wiley期刊有限责任公司代表美国骨与矿物研究学会(ASBMR)出版。
The development of Wnt‐based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co‐inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild‐type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors.Journal of Bone and Mineral Researchpublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).