Metformin Stimulates Osteoprotegerin and Reduces RANKL Expression in Osteoblasts and Ovariectomized Rats
Metformin Stimulates Osteoprotegerin and Reduces RANKL Expression in Osteoblasts and Ovariectomized Rats
复制标题
二甲双胍刺激骨保护素并降低成骨细胞和卵巢切除大鼠中 RANKL 的表达
DOI：
10.1002/jcb.23206
复制
发表时间：
2011-10-01
影响因子：
4
通讯作者：
Bai, Xiao-Chun
中科院分区：
文献类型：
--
作者：
Mai, Qi-Guang;Zhang, Zhong-Min;Bai, Xiao-Chun
抗糖尿病药物二甲双胍已被证明在体外增强成骨细胞分化和抑制破骨细胞分化，并防止卵巢切除（OVX）大鼠的骨丢失。但二甲双胍调节破骨细胞生成的机制尚不清楚。骨保护素（OPG）和核因子κ B受体激活因子配体（RANKL）是主要由成骨细胞分泌的细胞因子，在破骨细胞的分化和功能中起关键作用。在这项研究中，我们证明了二甲双胍剂量依赖性地刺激OPG并降低小鼠颅骨成骨细胞和成骨细胞系MC 3 T3-E1中RANKL mRNA和蛋白的表达。二甲双胍的两个靶点AMP活化蛋白激酶（AMPK）和CaM激酶激酶（CaMKK）的抑制可抑制成骨细胞内源性和二甲双胍诱导的OPG分泌。此外，二甲双胍处理的成骨细胞上清液减少了Raw 264.7细胞中抗酒石酸酸性磷酸酶（TRAP）阳性多核细胞的形成。最重要的是，二甲双胍显著增加了OVX大鼠近端胫骨的全身骨密度，防止了骨丢失，减少了TRAP阳性细胞，伴随着OPG的增加和RANKL表达的减少。这些体内和体外研究表明，二甲双胍可降低成骨细胞中的RANKL并刺激OPG表达，进一步抑制破骨细胞分化并预防OVX大鼠的骨丢失。J.细胞。112：2902-2909，2011. (C)2011 Wiley-Liss，Inc.
Anti-diabetic drug metformin has been shown to enhance osteoblasts differentiation and inhibit osteoclast differentiation in vitro and prevent bone loss in ovariectomized (OVX) rats. But the mechanisms through which metformin regulates osteoclastogensis are not known. Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) are cytokines predominantly secreted by osteoblasts and play critical roles in the differentiation and function of osteoclasts. In this study, we demonstrated that metformin dose-dependently stimulated OPG and reduced RANKL mRNA and protein expression in mouse calvarial osteoblasts and osteoblastic cell line MC3T3-E1. Inhibition of AMP-activated protein kinase (AMPK) and CaM kinase kinase (CaMKK), two targets of metformin, suppressed endogenous and metformin-induced OPG secretion in osteoblasts. Moreover, supernatant of osteoblasts treated with metformin reduced formation of tartrate resistant acid phosphatase (TRAP)-positive multi-nucleated cells in Raw264.7 cells. Most importantly, metformin significantly increased total body bone mineral density, prevented bone loss and decreased TRAP-positive cells in OVX rats proximal tibiae, accompanied with an increase of OPG and decrease of RANKL expression. These in vivo and in vitro studies suggest that metformin reduces RANKL and stimulates OPG expression in osteoblasts, further inhibits osteoclast differentiation and prevents bone loss in OVX rats. J. Cell. Biochem. 112: 2902-2909, 2011. (C) 2011 Wiley-Liss, Inc.