Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation.
Smurf1 inhibits mesenchymal stem cell proliferation and differentiation into osteoblasts through JunB degradation.
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DOI：
10.1002/jbmr.28
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发表时间：
2010-06
影响因子：
6.2
通讯作者：
Xing, Lianping
中科院分区：
文献类型：
--
作者：
Zhao, Lan;Huang, Jian;Guo, Ruolin;Wang, Yi;Chen, Di;Xing, Lianping
泛素连接酶Smurf 1缺陷小鼠以年龄依赖性方式发展骨量增加表型。据报道，这种骨量增加与分化的成骨细胞活性增强有关。虽然成骨细胞是间充质干细胞（MSC）的起源和MSC的增殖和分化可以对骨形成有显着的影响，它仍然在很大程度上是未知的MSC的调节是否在Smurf 1缺陷小鼠的骨量增加中发挥作用。在这项研究中，我们发现来自Smurf 1 −/−小鼠的骨髓间充质祖细胞形成了显着增加的碱性磷酸酶阳性集落，表明MSC增殖和分化在Smurf 1 −/−小鼠骨量增加中的作用。有趣的是，Smurf 1 −/−细胞中AP-1转录因子JunB的蛋白水平升高。生化实验表明，Smurf 1通过PY基序与JunB相互作用，并靶向JunB蛋白进行泛素化和蛋白酶体降解。事实上，Smurf 1缺陷的MSC具有更高的增殖率，这与Smurf 1 −/−细胞中细胞周期蛋白D1 mRNA和蛋白质都增加以及JunB可以诱导细胞周期蛋白D1启动子的事实一致。此外，JunB过表达诱导成骨细胞分化，表现为成骨细胞标志物的更高表达，JunB敲低不仅降低成骨细胞分化，而且使Smurf 1 −/−细胞的成骨潜力恢复到野生型水平。总之，我们的研究结果表明，Smurf 1负调控MSC的增殖和分化，通过控制JunB营业额通过泛素-蛋白酶体途径。© 2010美国骨与矿物质研究学会。
Ubiquitin ligase Smurf1-deficient mice develop an increased-bone-mass phenotype in an age-dependent manner. It was reported that such a bone-mass increase is related to enhanced activities of differentiated osteoblasts. Although osteoblasts are of mesenchymal stem cell (MSC) origin and MSC proliferation and differentiation can have significant impacts on bone formation, it remains largely unknown whether regulation of MSCs plays a role in the bone-mass increase of Smurf1-deficient mice. In this study we found that bone marrow mesenchymal progenitor cells from Smurf1−/− mice form significantly increased alkaline phosphatase–positive colonies, indicating roles of MSC proliferation and differentiation in bone-mass accrual of Smurf1−/− mice. Interestingly, Smurf1−/− cells have an elevated protein level of AP-1 transcription factor JunB. Biochemical experiments demonstrate that Smurf1 interacts with JunB through the PY motif and targets JunB protein for ubiquitination and proteasomal degradation. Indeed, Smurf1-deficient MSCs have higher proliferation rates, consistent with the facts that cyclin D1 mRNA and protein both are increased in Smurf1−/− cells and JunB can induce cyclinD1 promoter. Moreover, JunB overexpression induces osteoblast differentiation, shown by higher expression of osteoblast markers, and JunB knock-down not only decreases osteoblast differentiation but also restores the osteogenic potential to wild-type level in Smurf1−/− cells. In conclusion, our results suggest that Smurf1 negatively regulates MSC proliferation and differentiation by controlling JunB turnover through an ubiquitin-proteasome pathway. © 2010 American Society for Bone and Mineral Research.
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