miR-181a promotes osteoblastic differentiation through repression of TGF-β signaling molecules
miR-181a promotes osteoblastic differentiation through repression of TGF-β signaling molecules
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DOI：
10.1016/j.biocel.2012.12.008
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发表时间：
2013-03-01
影响因子：
4
通讯作者：
Knaus, Petra
中科院分区：
文献类型：
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作者：
Bhushan, Raghu;Gruenhagen, Johannes;Knaus, Petra
成骨细胞的分化受多种信号通路和相关关键转录因子的复杂相互作用以及microRNAs（miRNAs）的调控。在我们目前的研究中，我们发现miR-181 a在BMP诱导的C2 C12和MC 3 T3细胞成骨分化过程中高度上调。miR-181 a的过表达导致成骨细胞分化的关键标志物的上调以及ALP水平和茜素红染色的增强，表明该miRNA对于成骨细胞分化的重要性。此外，我们发现miR-181亚型（181 a，181 b，181 c）在小鼠颅骨和胫骨发育的不同阶段表达，这意味着它们在软骨内骨化和膜内骨化中的作用。我们发现miR-181 a的几个直接和间接靶点通过全局mRNA表达谱下调。我们的研究结果表明，miR-181 a通过靶向成骨细胞分化的负调节因子Tgfbi（TGF-β诱导的）和T β R-I/Alk 5（TGF-β I型受体），通过抑制TGF-β信号分子促进成骨细胞分化。此外，我们的研究结果表明Rgs 4和Gata 6是miR-181 a的直接靶点。综上所述，我们为特定的miRNA，miR-181 a和成骨细胞分化之间的关键功能联系提供了证据。(c)2012爱思唯尔有限公司保留所有权利。
Osteoblastic differentiation is controlled by complex interplay of several signaling pathways and associated key transcription factors, as well as by microRNAs (miRNAs). In our current study, we found miR-181a to be highly upregulated during BMP induced osteoblastic differentiation of C2C12 and MC3T3 cells. Overexpression of miR-181a led to upregulation of key markers of osteoblastic differentiation as well as enhanced ALP levels and Alizarin red staining, indicating the importance of this miRNA for osteoblastic differentiation. Further, we show that miR-181 isoforms (181a, 181b, 181c) are expressed during different stages of mouse calvarial and tibial development, implying their role in both endochondral and intramembranous ossification. We found several direct and indirect targets of miR-181a to be downregulated by global mRNA expression profiling. Our results demonstrate that miR-181a promotes osteoblastic differentiation via repression of TGF-beta signaling molecules by targeting the negative regulator of osteoblastic differentiation Tgfbi (Tgf-beta induced) and T beta R-I/Alk5 (TGF-beta type I receptor). Furthermore, our findings suggest that Rgs4 and Gata6 are direct targets of miR-181a. Taken together, we provide evidence for a crucial functional link between a specific miRNA, miR-181a and osteoblastic differentiation. (c) 2012 Elsevier Ltd. All rights reserved.