Sprouty2 is involved in the control of osteoblast proliferation and differentiation through the FGF and BMP signaling pathways
Sprouty2 is involved in the control of osteoblast proliferation and differentiation through the FGF and BMP signaling pathways
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DOI：
10.1002/cbin.10876
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发表时间：
2018-09-01
影响因子：
3.9
通讯作者：
Nakamura, Seiji
中科院分区：
文献类型：
--
作者：
Taketomi, Takaharu;Onimura, Tomohiro;Nakamura, Seiji
成纤维细胞生长因子（FGF）和骨形态发生蛋白（BMP）通过细胞外信号调节激酶1/2（ERK 1/2）和Smad途径在骨形成和成骨细胞活性中起重要作用。Sprouty家族成员是FGF信号传导途径的细胞内抑制剂，并且已经在哺乳动物中鉴定了Sprouty的四种直系同源物。体内分析显示Sprouty 2与骨形成相关。然而，Sprouty家族控制骨形成的机制尚未阐明。在这项研究中，我们研究了Sprouty 2在成骨细胞增殖和分化中的作用。我们检测了MC 3 T3-E1细胞中Sprouty 2的表达，发现碱性FGF刺激诱导了高水平的Sprouty 2表达。与对照细胞相比，Sprouty 2在MC 3 T3-E1细胞中的过表达导致增殖抑制。Sprouty 2在碱性FGF刺激后负调节ERK 1/2的磷酸化，在BMP刺激后负调节Smad 1/5/8的磷酸化。此外，Sprouty 2抑制osterix、碱性磷酸酶和骨钙素mRNA的表达，这些是成骨细胞分化的标志物。此外，Sprouty 2抑制成骨细胞基质矿化。这些结果表明，Sprouty 2通过下调FGF-ERK 1/2和BMP-Smad通路参与成骨细胞增殖和分化的控制，并抑制成骨细胞分化标志物的诱导。
Fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) play essential roles in bone formation and osteoblast activity through the extracellular signal-regulated kinase 1/2 (ERK1/2) and Smad pathways. Sprouty family members are intracellular inhibitors of the FGF signaling pathway, and four orthologs of Sprouty have been identified in mammals. In vivo analyses have revealed that Sprouty2 is associated with bone formation. However, the mechanism by which the Sprouty family controls bone formation has not been clarified. In this study, we investigated the involvement of Sprouty2 in osteoblast proliferation and differentiation. We examined Sprouty2 expression in MC3T3-E1 cells, and found that high levels of Sprouty2 expression were induced by basic FGF stimulation. Overexpression of Sprouty2 in MC3T3-E1 cells resulted in suppressed proliferation compared with control cells. Sprouty2 negatively regulated the phosphorylation of ERK1/2 after basic FGF stimulation, and of Smad1/5/8 after BMP stimulation. Furthermore, Sprouty2 suppressed the expression of osterix, alkaline phosphatase, and osteocalcin mRNA, which are markers of osteoblast differentiation. Additionally, Sprouty2 inhibited osteoblast matrix mineralization. These results suggest that Sprouty2 is involved in the control of osteoblast proliferation and differentiation by downregulating the FGF-ERK1/2 and BMP-Smad pathways, and suppresses the induction of markers of osteoblast differentiation.