M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation.
M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation.
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DOI：
10.1016/j.yexcr.2009.09.028
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发表时间：
2010-02
影响因子：
3.7
通讯作者：
H. Watanabe-Takano;K. Takano;E. Keduka;T. Endo
中科院分区：
文献类型：
--
作者：
H. Watanabe-Takano;K. Takano;E. Keduka;T. Endo
小的GTCM-Ras在中枢神经系统中高度表达，并且在神经元分化中起重要作用。然而，它的其他细胞和生理功能仍有待阐明。在这里，我们阐明了新的功能M-Ras在成骨。M-Ras在发育中的小鼠骨中显著表达，特别是在成骨细胞和肥大软骨细胞中。在C3 H/10 T1/2（10 T1/2）间充质细胞和MC 3 T3-E1前成骨细胞分化为成骨细胞的过程中，其表达升高。用骨形态发生蛋白-2（BMP-2）处理C2 C12骨骼肌成肌细胞以使其转分化为成骨细胞也诱导M-Ras mRNA和蛋白表达。此外，BMP-2处理激活了M-Ras蛋白。在10 T1/2细胞中稳定表达具有组成性活性的M-Ras（G22 V）促进成骨细胞分化。M-Ras（G22 V）也诱导C2 C12细胞转分化为成骨细胞。相反，通过RNAi敲低内源性M-Ras干扰10 T1/2和MC 3 T3-E1细胞中的成骨细胞分化。用p38 MAP激酶（MAPK）和c-Jun N-末端激酶（JNK）抑制剂处理表达M-Ras（G22 V）的C2 C12细胞，但不受MAPK和ERK激酶（MEK）或磷脂酰肌醇3-激酶抑制剂的抑制。这些结果表明，M-Ras，诱导和激活BMP-2信号，参与成骨细胞的决定，分化，并在p38 MAPK和JNK调节下的转分化。
The small GTPase M-Ras is highly expressed in the central nervous system and plays essential roles in neuronal differentiation. However, its other cellular and physiological functions remain to be elucidated. Here, we clarify the novel functions of M-Ras in osteogenesis. M-Ras was prominently expressed in developing mouse bones particularly in osteoblasts and hypertrophic chondrocytes. Its expression was elevated in C3H/10T1/2 (10T1/2) mesenchymal cells and in MC3T3-E1 preosteoblasts during differentiation into osteoblasts. Treatment of C2C12 skeletal muscle myoblasts with bone morphogenetic protein-2 (BMP-2) to bring about transdifferentiation into osteoblasts also induced M-Ras mRNA and protein expression. Moreover, the BMP-2 treatment activated the M-Ras protein. Stable expression of the constitutively active M-Ras(G22V) in 10T1/2 cells facilitated osteoblast differentiation. M-Ras(G22V) also induced transdifferentiation of C2C12 cells into osteoblasts. In contrast, knockdown of endogenous M-Ras by RNAi interfered with osteoblast differentiation in 10T1/2 and MC3T3-E1 cells. Osteoblast differentiation in M-Ras(G22V)-expressing C2C12 cells was inhibited by treatment with inhibitors of p38 MAP kinase (MAPK) and c-Jun N-terminal kinase (JNK) but not by inhibitors of MAPK and ERK kinase (MEK) or phosphatidylinositol 3-kinase. These results imply that M-Ras, induced and activated by BMP-2 signaling, participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation.