Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.
Discipline of Paediatrics and Child Health, Sydney Medical School, University of Sydney, Sydney, Australia.
J Bone Miner Res. 2018 Mar;33(3):486-498. doi: 10.1002/jbmr.3330. Epub 2017 Nov 29.
Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β-catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl-Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl-Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl-Ab therapy. To address this, we carried out a 2-week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl-Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl-Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β-catenin gene expression were found with tibial loading, however not with Scl-Ab treatment alone. Notably, the combination of load and Scl-Ab elicited a synergistic response from a number of specific Wnt-related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl-Ab or loading treatment alone. The Wnt/β-catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research.
骨硬化蛋白（一种 Wnt/β-catenin 信号传导的内源性抑制剂）活性或表达降低会导致骨形成和骨量增加。靶向并中和骨硬化蛋白的抗体（Scl-Ab）已被证明可增加骨量并降低骨折风险。骨硬化蛋白在调节骨骼对其生物力学环境变化的反应方面也很重要。然而，Scl-Ab 对机械转导的影响尚不清楚，有人推测接受 Scl-Ab 治疗的个体的加载反应可能会改变。为了解决这个问题，我们对接受载体或 100mg/kg/周 Scl-Ab 治疗的 C57Bl/6 小鼠进行了为期 2 周的胫骨周期性压缩加载研究。研究发现，加载可增加骨体积、密度和动态骨形成，并且加载和 Scl-Ab 的组合进一步增加了合成代谢反应。为了研究潜在的机制，我们对来自所有四个实验组的小鼠的胫骨进行了 RNA 测序（RNAseq）基因谱分析。研究发现，胫骨加载会导致 Wnt/β-catenin 基因表达的主要改变，但单独使用 Scl-Ab 治疗则不会。值得注意的是，负载和 Scl-Ab 的组合引起了许多特定的 Wnt 相关和机械转导因子的协同反应。一个意外的发现是，组合治疗会显著上调 Rho GTPase 信号通路中的因子。总之，联合治疗比单独使用 Scl-Ab 或加载治疗具有更深远的合成代谢反应。Wnt/β-catenin 和 Rho GTPase 途径参与了骨骼机械转导，支持了骨骼机械转导可能包含许多相互关联的信号通路的概念。
