A microRNA regulatory mechanism of osteoblast differentiation
A microRNA regulatory mechanism of osteoblast differentiation
复制标题
DOI：
10.1073/pnas.0909311106
复制
发表时间：
2009-12-08
影响因子：
11.1
通讯作者：
Takeda, Shu
中科院分区：
文献类型：
--
作者：
Inose, Hiroyuki;Ochi, Hiroki;Takeda, Shu
越来越多的证据表明microRNAs（miRNAs）在脊椎动物和无脊椎动物中调节各种发育和稳态事件。成骨细胞分化是骨骼正常发育和获得骨量的关键步骤;然而，非编码小RNA，特别是miRNA在成骨细胞分化中的生理作用仍然难以捉摸。在这里，通过对成骨细胞分化过程中miRNA表达的全面分析，我们发现miR-206，以前被认为是肌肉特异性miRNA，是这一过程的关键调节因子。miR-206在成骨细胞中表达，并且其表达随着成骨细胞分化而降低。miR-206在成骨细胞中的过表达抑制其分化，相反，miR-206表达的敲低促进成骨细胞分化。计算机模拟分析和分子实验显示，连接蛋白43（Cx43），成骨细胞中的主要间隙连接蛋白，作为miR-206的靶点，并且在表达miR-206的成骨细胞中恢复Cx43表达使其免于miR-206对成骨细胞分化的抑制作用。最后，在成骨细胞中表达miR-206的转基因小鼠由于成骨细胞分化受损而形成低骨量表型。我们的数据表明，miRNA是成骨细胞分化的调节因子。
Growing evidence shows that microRNAs (miRNAs) regulate various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; however, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast differentiation remains elusive. Here, through comprehensive analysis of miRNAs expression during osteoblast differentiation, we show that miR-206, previously viewed as a musclespecific miRNA, is a key regulator of this process. miR-206 was expressed in osteoblasts, and its expression decreased over the course of osteoblast differentiation. Overexpression of miR-206 in osteoblasts inhibited their differentiation, and conversely, knockdown of miR-206 expression promoted osteoblast differentiation. In silico analysis and molecular experiments revealed connexin 43 (Cx43), a major gap junction protein in osteoblasts, as a target of miR-206, and restoration of Cx43 expression in miR-206-expressing osteoblasts rescued them from the inhibitory effect of miR-206 on osteoblast differentiation. Finally, transgenic mice expressing miR-206 in osteoblasts developed a low bone mass phenotype due to impaired osteoblast differentiation. Our data show that miRNA is a regulator of osteoblast differentiation.