Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation.
Risedronate inhibits bone marrow mesenchymal stem cell adipogenesis and switches RANKL/OPG ratio to impair osteoclast differentiation.
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DOI：
10.1016/j.jss.2012.03.018
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
Jian Jin;Liang Wang;Xiaokai Wang;Pinglin Lai;Min-jun Huang;D. Jin;Zhao-Ming Zhong;Jianting Chen;X. Bai
中科院分区：
文献类型：
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作者：
Jian Jin;Liang Wang;Xiaokai Wang;Pinglin Lai;Min-jun Huang;D. Jin;Zhao-Ming Zhong;Jianting Chen;X. Bai
背景骨质疏松伴随着骨髓脂肪组织的增多。骨髓成脂作用已成为预防骨丢失的治疗靶点。氨基双膦酸盐已被广泛用于治疗骨质疏松症，但氨基双膦酸盐抑制骨质疏松的机制尚不清楚。本研究的目的是在骨髓微环境中观察双膦酸类化合物对骨髓成脂的影响以及脂肪细胞产生的破骨细胞因子。每个细胞样本在有或没有成脂诱导的情况下增加利塞膦酸浓度14d，然后分析分化后的脂肪细胞的液滴。用免疫印迹和酶联免疫吸附试验检测脂肪细胞产生的核因子-κB受体激活剂配体和护骨素，以及前破骨细胞炎症因子IL-1、IL-6和肿瘤坏死因子α的水平。结果利塞膦酸钠不仅剂量依赖性地抑制人骨髓间充质干细胞的成脂作用，而且还抑制核因子κB配体受体激活剂，而不是骨保护素在分化脂肪细胞中的表达，以及促破骨细胞炎症因子的表达。结论利塞膦酸影响骨髓脂肪细胞-破骨细胞之间的串扰，为利塞膦酸抗骨质疏松作用提供了一种新的机制。
BACKGROUNDOsteoporosis is accompanied by an increase in bone marrow adipose tissue. Bone marrow adipogenesis has emerged as a therapeutic target for prevention of bone loss. Amino-bisphosphonates have been widely used for treatment of osteoporosis, but the mechanism through which amino-bisphosphonates inhibit osteoporosis remains unclear. The purpose of this study is to investigate the effects of bisphosphonates on bone marrow adipogenesis and the pro-osteoclastic factors produced by adipocytes in bone marrow microenvironment.MATERIALS AND METHODSHuman mesenchymal stem cells were obtained and purified from six volunteer donors. Each sample of cells was treated by increasing concentrations of risedronate with or without adipogenic induction for 14 d, and then droplets of the differentiated adipocytes were analyzed. The level of receptor activator of nuclear factor-κB ligand and osteoprotegerin, as well as pro-osteoclastic inflammatory factors interleukin-1, interleukin-6, and tumor necrosis factor α produced by adipocytes were evaluated by Western blot and ELISA assay. Moreover, the effect of risedronate on the activity of mammalian target of rapamycin complex 1, a key Ser/Thr kinase for initiation of adipocyte differentiation, was investigated.RESULTSRisedronate not only dose-dependently inhibited the bone marrow adipogenesis from human mesenchymal stem cells but also suppressed receptor activator of nuclear factor-κB ligand, not osteoprotegerin, expression in differentiated adipocytes, as well as pro-osteoclastic inflammatory factors. Furthermore, the activity of mammalian target of rapamycin complex 1 was suppressed by risedronate.CONCLUSIONOur findings that risedronate influences the crosstalk between bone marrow adipocyte–osteoclast represent a novel mechanism for the anti-osteoporotic effects of risedronate.