Sun Tianhao, Li Zhaoyang, Zhong Xing, Cai Zhe, Ning Ziyu, Hou Tianheng, Xiong Lifeng, Feng Yu, Leung Frankie, Lu William W, Peng Songlin
Department of Spine Surgery, Shenzhen People's Hospital, Jinan University Second College of Medicine, Shenzhen, 518000, China.
Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
J Cell Commun Signal. 2019 Mar;13(1):85-97. doi: 10.1007/s12079-018-0478-y. Epub 2018 Jul 15.
Strontium is a drug with the bone formation and anti-resorption effects on bone. The underlying mechanisms for the dual effect of strontium on bone metabolism, especially for the anti-resorption effects remain unknown. Thus, we aim to investigate the mechanisms of effects of strontium on osteoclastogenesis. Firstly, we found that strontium decreased the levels of important biomarkers of receptor activator of nuclear factor kappa-B ligand (RANKL) which induced osteoclast differentiation, indicating that strontium might directly inhibit osteoclast differentiation. Next, we revealed that strontium enhanced Low Density Lipoprotein Receptor-Related Protein 6 (LRP6)/β-catenin/osteoprotegerin (OPG) signaling pathway in MC3T3-E1 cells. The signaling pathway may negatively regulate osteoclastogenesis. Thus, strontium indirectly inhibited RANKL induced osteoclast differentiation. Finally, we revealed that OPG was targeted by miR-181d-5p as determined by luciferase reporter assay and downregulated by miR-181d-5p at both mRNA and protein levels as determined by western blot.
锶是一种对骨骼具有成骨和抗骨吸收作用的药物。锶对骨代谢产生双重作用的潜在机制，尤其是抗骨吸收作用的机制尚不清楚。因此，我们旨在研究锶对破骨细胞生成的作用机制。首先，我们发现锶降低了诱导破骨细胞分化的核因子κB受体激活剂配体（RANKL）的重要生物标志物水平，表明锶可能直接抑制破骨细胞分化。接下来，我们发现锶增强了MC3T3-E1细胞中的低密度脂蛋白受体相关蛋白6（LRP6）/β-连环蛋白/骨保护素（OPG）信号通路。该信号通路可能对破骨细胞生成起负调节作用。因此，锶间接抑制RANKL诱导的破骨细胞分化。最后，通过荧光素酶报告基因检测确定OPG是miR-181d-5p的靶标，并且通过蛋白质印迹法确定在mRNA和蛋白质水平上均被miR-181d-5p下调。
