The Calcium-sensing Receptor (CaR) is Involved in Strontium Ranelate-induced Osteoblast Differentiation and Mineralization
The Calcium-sensing Receptor (CaR) is Involved in Strontium Ranelate-induced Osteoblast Differentiation and Mineralization
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DOI：
10.1055/s-0030-1255091
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发表时间：
2010-06
影响因子：
2.2
通讯作者：
Shin Takaoka;Toru Yamaguchi;S. Yano;M. Yamauchi;T. Sugimoto
中科院分区：
文献类型：
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作者：
Shin Takaoka;Toru Yamaguchi;S. Yano;M. Yamauchi;T. Sugimoto
众所周知，雷奈酸锶通过刺激骨形成和抑制骨吸收来降低骨质疏松症患者的骨折风险。然而，锶对骨骼产生这种有益作用的机制尚不清楚。我们研究了钙敏感受体(CAR)是否参与了这一机制，该受体被包括锶(2+)在内的二价阳离子激活。雷奈酸锶和氯化锶均可剂量依赖性地刺激瞬时转染人CAR的人胚胎肾293细胞中细胞外信号调节激酶(ERK)的磷酸化。雷奈酸锶还以剂量和时间依赖的方式刺激内源性表达CAR的小鼠成骨细胞MC3T3-E1中ERK的磷酸化。雷奈酸锶可促进MC3T3-E1细胞骨钙素和骨形态发生蛋白-2的基因表达，促进细胞矿化和增殖。CAR抑制剂NPS2390可几乎完全拮抗雷尼酸锶诱导的MC3T3-E1细胞矿化和增殖。这些结果表明，雷奈酸锶不仅通过激活CAR诱导成骨细胞的增殖，而且还通过激活CAR而促进成骨细胞的分化和矿化，证实了雷奈酸锶治疗骨质疏松的作用可能部分是通过CAR介导的。
Strontium ranelate is known to reduce fracture risk in osteoporotic patients by stimulating bone formation and suppressing bone resorption. However, the mechanism by which strontium exerts this beneficial effect on bone is unclear. We examined whether or not the calcium-sensing receptor (CaR), which is activated by divalent cations including Sr (2+), is involved in this mechanism. Both strontium ranelate and strontium chloride dose-dependently stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in Human Embryonic Kidney 293 cells transiently transfected with the human CaR. Strontium ranelate also dose- and time-dependently stimulated phosphorylation of ERK in mouse osteoblastic MC3T3-E1 cells expressing the CaR endogenously. Strontium ranelate increased mRNA expression of osteocalcin and bone morphogenetic protein-2 in MC3T3-E1 cells as well as mineralization and proliferation of the cells. Pretreatments of NPS2390, a CaR inhibitor, almost totally antagonized strontium ranelate-induced mineralization and proliferation of MC3T3-E1 cells. These findings indicate that strontium ranelate induces not only osteoblast proliferation but also its differentiation and mineralization by activating the CaR, and confirm that the therapeutic efficacy of strontium ranelate for osteoporosis may be partly mediated by the CaR.