Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion
Metformin protects bone mass in ultra-high-molecular-weight polyethylene particle-induced osteolysis by regulating osteocyte secretion
复制标题
二甲双胍通过调节骨细胞分泌保护超高分子量聚乙烯颗粒诱导的骨溶解中的骨量
DOI：
10.1007/s00774-018-0939-7
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发表时间：
2019-05-01
影响因子：
3.3
通讯作者：
Cao, Xiaorui
中科院分区：
文献类型：
--
作者：
Yan, Zhao;Zhu, Shu;Cao, Xiaorui
二甲双胍是一种用于治疗2型糖尿病的降糖药，最近发现它除了调节血糖外还有更多的作用。我们发现，在超高分子量聚乙烯颗粒诱导的骨溶解小鼠模型中，二甲双胍具有骨保护作用，并降低骨形成负调节因子硬化素（SOST）和Dickkopf相关蛋白1（DKK 1），增加骨保护素（OPG）分泌，增加OPG/核因子-κB受体激活剂配体（RANKL）的比值。在体外，我们建立了一个三维共培养系统，其中二甲双胍通过成熟骨细胞分泌影响成骨细胞和破骨细胞。50 μM蛋氨酸可显著降低SOST和DKK 1 mRNA的表达，促进碱性磷酸酶活性和成骨细胞增殖，增加OPG分泌和OPG/RANKL比值，抑制破骨细胞的生成。腺苷5′-磷酸活化蛋白激酶抑制剂化合物C可逆转此作用。我们的研究结果表明，二甲双胍诱导成骨细胞的分化和矿化，同时通过成熟骨细胞分泌抑制破骨细胞的生成。因此，该药物可能不仅对糖尿病有益，而且通过作用于成熟的骨细胞而对其他骨骼疾病有益。
Metformin, an anti-hyperglycemic agent used for type 2 diabetes, has recently been found to have more effects apart from glucose regulation. We found that, in ultra-high-molecular-weight polyethylene particle-induced osteolysis mouse models, metformin had bone protect property and reduced the negative regulator of bone formation sclerostin (SOST) and Dickkopf-related protein 1 (DKK1), and increased osteoprotegerin (OPG) secretion and the ratio of OPG/Receptor Activator for Nuclear Factor-κB Ligand (RANKL). In vitro, we established a 3D co-culture system in which metformin affects osteoblasts and osteoclasts through mature osteocytes secretion. Metformin (50 μM) significantly decreased SOST and DKK1 mRNA expression, stimulating alkaline phosphatase activity and proliferation of osteoblast, and increased OPG secretion and the ratio of OPG/RANKL, inhibiting osteoclastogenesis. Moreover, the effect on OPG was reversed by adenosine 5′-monophosphate-activated protein kinase inhibitor, Compound C. Our finding suggests that metformin induces differentiation and mineralization of osteoblasts, while inhibits osteoclastogenesis via mature osteocytes secretion. Therefore, the drug might be beneficial for not only diabetes but also in other bone disorders by acting on mature osteocytes.