Peng Songlin, Zhou Guangqian, Luk Keith D K, Cheung Kenneth M C, Li Zhaoyang, Lam Wing Moon, Zhou Zhongjun, Lu William W
Department of Orthopaedics and Traumatology, the University of Hong Kong, Hong Kong SAR.
Cell Physiol Biochem. 2009;23(1-3):165-74. doi: 10.1159/000204105. Epub 2009 Feb 18.
Strontium ralenate is a new anti-osteoporosis agent. The cellular and molecular mechanism underlying the anabolic effect of strontium on bone remains to be elucidated. Osteoblasts, the main bone forming cells are known to be derived from bone marrow mesenchymal stem cells (MSCs). The present study therefore aimed to investigate the possible effects of strontium on MSCs and signaling pathways possibly involved. It was firstly demonstrated that strontium treatment significantly increased osteoblast-related gene expression and alkaline phosphatase (ALP) of osteogenic-differentiating MSCs. Accompanying the enhanced osteogenic differentiation, the increased phosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2 and p38 was detected in strontium-treated MSCs. PD98059 and SB203580, selective inhibitors of ERK1/2 kinase and p38, attenuated the effect of strontium on osteogenesis. Furthermore, it was demonstrated that Rat Sarcoma viral oncogene homolog (RAS), an upstream regulator of ERK1/2 and p38, was activated by strontium treatment and siRNA-mediated Ras knockdown inhibited strontium-stimulated expression of osteogenic markers. Finally, the transcriptional activity and phosphorylation level of Runx2 was significantly increased in response to strontium treatment in MSCs. PD98059 and Ras siRNA inhibited the effect of strontium on Runx2 activation. Taken together, these results indicated that strontium can promote osteogenic differentiation of MSCs through activating the Ras/MAPK signaling pathway and the downstream transcription factor Runx2.
雷奈酸锶是一种新型抗骨质疏松药物。锶对骨骼合成代谢作用的细胞和分子机制仍有待阐明。成骨细胞是主要的骨形成细胞，已知其来源于骨髓间充质干细胞（MSC）。因此，本研究旨在探讨锶对MSC的可能影响以及可能涉及的信号通路。首先证明，锶处理显著增加了成骨分化的MSC中与成骨细胞相关的基因表达和碱性磷酸酶（ALP）。随着成骨分化增强，在锶处理的MSC中检测到丝裂原活化蛋白激酶（MAPK）ERK1/2和p38的磷酸化增加。ERK1/2激酶和p38的选择性抑制剂PD98059和SB203580减弱了锶对成骨的作用。此外，还证明了作为ERK1/2和p38上游调节因子的大鼠肉瘤病毒癌基因同源物（RAS）被锶处理激活，并且siRNA介导的Ras敲低抑制了锶刺激的成骨标志物表达。最后，在MSC中，响应于锶处理，Runx2的转录活性和磷酸化水平显著增加。PD98059和Ras siRNA抑制了锶对Runx2激活的作用。综上所述，这些结果表明锶可通过激活Ras/MAPK信号通路和下游转录因子Runx2促进MSC的成骨分化。
