Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms
Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms
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DOI：
10.1016/j.bone.2008.02.010
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发表时间：
2008-06-01
期刊：
影响因子：
4.1
通讯作者：
Caverzasio, Joseph
中科院分区：
文献类型：
--
作者：
Caverzasio, Joseph
雷奈酸锶诱导成骨细胞复制的细胞和分子机制目前正在研究中。钙感应受体是一个被建议的靶点，但其他潜在的机制还没有被研究。在成骨前细胞MC3T3-E1和多能间充质C3H10T1/2细胞中，研究了雷尼酸锶诱导复制的信号通路。比较了雷尼酸锶和氯化钙作为钙离子的作用。在MCM-E1细胞中，雷奈酸锶呈剂量依赖性增加细胞数，而CaCl2无此作用；而在C3H10T1/2细胞中，两种阳离子的作用相似。免疫印迹分析表明，与CaCl2相比，雷奈酸锶对MCM-E1细胞ERK、PKC和PKD的激活延迟。事实上，雷奈酸锶在一小时或几小时后就开始发出信号，而CaCl2在暴露5分钟后就已经有了最大的影响。在C3H10T1/2细胞中，雷奈酸锶诱导了两种类型的信号，一种是快速效应，另一种是延迟反应。除了激活ERK、PKC和PKD外，雷奈酸锶和CaCl2还瞬时激活了C3H10T1/2细胞中的p38。特异性抑制剂的功能分析表明，雷奈酸锶诱导的细胞复制涉及MC3T3-E1细胞的PKC/PKD通路和C3H10T1/2细胞的p38通路。在这两种类型的细胞中，ERK通路的抑制减少了基础细胞的复制，但不会对雷尼酸锶的反应产生影响。总之，雷奈酸锶通过两种不同的细胞机制增加成骨细胞系细胞的复制。雷奈酸锶可能直接与CaSR相互作用，在C3H10T1/2细胞中触发p38等促有丝分裂信号。然而，在这两种细胞系中，几个信号通路的延迟激活表明雷尼酸锶释放了一种自分泌生长因子，这代表了另一种诱导成骨细胞复制的潜在机制。(C)2008 Elsevier Inc.保留所有权利。
The cellular and molecular mechanisms involved in osteoblastic cell replication induced by strontium ranelate are presently under investigation. The calcium-sensing receptor is a suggested target but other potential mechanisms have not been investigated. Signaling pathways involved in strontium ranelate-induced replication were investigated in preosteoblastic MC3T3-E1 and pluripotent mesenchymal C3H10T1/2 cells. Strontium ranelate effects were compared with those of calcium chloride as Ca2+. In MCM-E1 cells, strontium ranelate but not CaCl2 dose-dependently increased cell number whereas similar effects were observed for both cations in C3H10T1/2 cells. Immunoblot analysis indicated that activation of ERK, PKC and PKD by strontium ranelate in MCM-E1 cells was delayed compared with CaCl2. Indeed, onset of signaling by strontium ranelate was detected after one or several hours whereas CaCl2 had a maximal effect already after 5 min exposure. In C3H10T1/2 cells, strontium ranelate induced two types of signaling, a rapid effect and a delayed response. In addition to activation of ERK, PKC and PKD, strontium ranelate and CaCl2 also transiently activated p38 in C3H10T1/2 cells. Functional analysis with specific inhibitors indicated that cell replication induced by strontium ranelate involves a PKC/PKD pathway in MC3T3-E1 cells and p38 in C3H10T1/2 cells. In both cell types, inhibition of the ERK pathway decreased basal cell replication but not the strontium ranelate response. In conclusion, strontium ranelate increases the replication of cells of the osteoblastic lineage by two distinct cellular mechanisms. Strontium ranelate may directly interact with the CaSR and trigger mitogenic signals such as p38 in C3H10T1/2 cells. The delayed activation of several signaling pathways in both cell lines, however, suggests the release of an autocrine growth factor by strontium ranelate that represents another potential mechanism for inducing osteoblastic cell replication. (C) 2008 Elsevier Inc. All rights reserved.