Mechanobiology and Medical Devices Research Group (MMDRG), Centre for Biomechanics Research (BioMEC), Biomedical Engineering, College of Engineering and Informatics, National University of Ireland Galway, Galway, Ireland.
Early Solutions, UCB Pharma, Slough, UK.
BMC Mol Cell Biol. 2020 Nov 4;21(1):78. doi: 10.1186/s12860-020-00322-w.
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.
抗硬骨素抗体（Scl-Ab）已显示出在动物研究和临床试验中诱导骨形成和减少骨吸收、增加骨强度和大幅降低骨折风险的巨大潜力。机械负荷负调节硬骨素的表达，并且硬骨素已被证明能诱导破骨细胞合成 RANKL。然而，Scl-Ab 如何调控破骨细胞分化和功能尚不完全清楚。我们最近发现，成骨细胞和破骨细胞在雌激素缺乏时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加剧。然而，目前尚不清楚雌激素缺乏的破骨细胞是否会加剧破骨细胞生成。本研究的目的是：（1）确定破骨细胞在体外雌激素缺乏时是否诱导破骨细胞生成和骨吸收；（2）研究 Scl-Ab 是否可以通过减弱 RANKL/OPG 表达来逆转破骨细胞生成和吸收。
通过条件培养基和共培养实验，我们发现雌激素缺乏条件下破骨细胞诱导的破骨细胞生成和骨吸收增加。这是第一项研究报道，Scl-Ab 给药能够通过降低雌激素缺乏破骨细胞中 RANKL/OPG 比值的表达和增加 WISP1 的表达来逆转破骨细胞生成和吸收。
本研究通过揭示 Scl-Ab 能够减少破骨细胞与破骨细胞之间的促破骨细胞生成细胞信号，从而增强了对体内观察到 Scl-Ab 治疗后骨吸收减少的生物学变化的理解。
