Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. However, how Scl-Ab governs osteocyte regulation of osteoclast differentiation and function is not fully understood. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG expression. Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab has the ability to revert osteocyte-mediated osteoclastogenesis and resorption by decreasing RANKL/OPG ratio expression and increasing WISP1 expression in estrogen deficient osteocytes. This study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.

中文翻译：

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Scl-Ab逆转雌激素缺乏性骨细胞中破骨细胞的信号转导和吸收

在动物研究和临床试验中，针对硬化蛋白的中和抗体（Scl-Ab）在诱导骨骼形成和减少骨骼吸收，增加强度以及显着降低骨折风险方面显示出巨大潜力。机械负荷负调节硬化素的表达，并且已经证明硬化素诱导骨细胞中RANKL的合成。但是，尚不完全了解Scl-Ab如何控制破骨细胞分化和功能的骨细胞调节。我们最近发现，在雌激素缺乏时，成骨细胞和成骨细胞会改变破骨细胞生成信号（RANKL / OPG），并且成骨细胞诱导的破骨细胞生成和吸收会加剧。但是，雌激素缺乏的骨细胞是否会加剧破骨细胞形成尚不明确。这项研究的目的是（1）建立在体外雌激素缺乏期间骨细胞是否诱导破骨细胞生成和骨吸收（2）研究硬化蛋白抗体是否可以通过减弱RANKL / OPG表达来逆转骨细胞介导的破骨细胞形成和吸收。使用条件培养基和共培养实验，我们发现在雌激素缺乏的情况下，骨细胞诱导的破骨细胞增多和骨吸收增加。这是第一个报道，通过减少雌激素缺乏的骨细胞中的RANKL / OPG比表达和增加WISP1表达，Scl-Ab的给药具有恢复骨细胞介导的破骨细胞生成和吸收的能力。