Rictor is required for optimal bone accrual in response to anti-sclerostin therapy in the mouse.
Rictor is required for optimal bone accrual in response to anti-sclerostin therapy in the mouse.
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Rictor 对于小鼠抗硬化素治疗的最佳骨生成是必需的。
DOI：
10.1016/j.bone.2016.01.013
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发表时间：
2016-04
期刊：
影响因子：
4.1
通讯作者：
Long F
中科院分区：
文献类型：
--
作者：
Sun W;Shi Y;Lee WC;Lee SY;Long F
Wnt信号通路已成为开发新型骨合成代谢疗法的一个主要靶向通路。针对分泌型Wnt拮抗剂硬骨素的中和抗体（Scl - Ab）在动物模型和人类中均可增加骨量。因为我们之前已表明，依赖Rictor的mTORC2活性有助于Wnt信号传导，在此我们测试Rictor对于Scl - Ab促进骨合成代谢是否是必需的。在早期胚胎肢端间充质中缺失Rictor的小鼠（Prx1 - Cre；Rictorf/f，以下简称RiCKO）从4个月龄开始接受Scl - Ab治疗5周。治疗前的体内微计算机断层扫描（μCT）分析显示，RiCKO小鼠显示出正常的骨小梁，但皮质骨量比同窝对照小鼠少。经过5周治疗后，Scl - Ab在对照组和RiCKO小鼠中均呈剂量依赖性地增加骨小梁和皮质骨量，但在RiCKO小鼠中增加幅度明显减弱。动态组织形态计量学显示，RiCKO小鼠对Scl - Ab的反应中形成的骨量比对照组少。此外，在基础条件下，RiCKO小鼠的破骨细胞比正常小鼠少，并且Scl - Ab对破骨细胞数量的抑制作用也较小。与体内破骨细胞较少一致的是，来自RiCKO小鼠的骨髓基质细胞（BMSC）表达的Rankl较少，但Opg或M - CSF水平正常，并且在体外支持破骨细胞生成方面不如对照细胞有效。Rankl对Rictor的依赖似乎独立于Wnt - β - 连环蛋白或Wnt - mTORC2信号通路，因为Wnt3a对来自对照组或RiCKO小鼠的BMSC的Rankl表达没有影响。总体而言，肢端间充质谱系中的Rictor对于抗硬骨素治疗在骨形成和骨吸收方面的正常反应是必需的。
Wnt signaling has emerged as a major target pathway for the development of novel bone anabolic therapies. Neutralizing antibodies against the secreted Wnt antagonist sclerostin (Scl-Ab) increase bone mass in both animal models and humans. Because we have previously shown that Rictor-dependent mTORC2 activity contributes to Wnt signaling, we test here whether Rictor is required for Scl-Ab to promote bone anabolism. Mice with Rictor deleted in the early embryonic limb mesenchyme (Prx1-Cre;Rictorf/f, hereafter RiCKO) were subjected to Scl-Ab treatment for 5 weeks starting at 4 months of age. In vivo micro–computed tomography (μCT) analyses before the treatment showed that the RiCKO mice displayed normal trabecular, but less cortical bone mass than the littermate controls. After 5 weeks of treatment, Scl-Ab dose-dependently increased trabecular and cortical bone mass in both control and RiCKO mice, but the increase was significantly blunted in the latter. Dynamic histomorphometry revealed that the RiCKO mice formed less bone than the control in response to Scl-Ab. In addition, the RiCKO mice possessed fewer osteoclasts than normal under the basal condition and exhibited lesser suppression in osteoclast number by Scl-Ab. Consistent with the fewer osteoclasts in vivo, bone marrow stromal cells (BMSC) from the RiCKO mice expressed less Rankl but normal levels of Opg or M-CSF, and were less effective than the control cells in supporting osteoclastogenesis in vitro. The reliance of Rankl on Rictor appeared to be independent of Wnt-β-catenin or Wnt-mTORC2 signaling as Wnt3a had no effect on Rankl expression by BMSC from either control or RICKO mice. Overall, Rictor in the limb mesenchymal lineage is required for the normal response to the anti-sclerostin therapy in both bone formation and resorption.