MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation.
MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation.
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作者：
Huang, Jian;Zhao, Lan;Xing, Lianping;Chen, Di
间充质干细胞分化为特定谱系受到严格调控，这种调控的功能障碍可能导致病理后果。骨质疏松症患者脂肪细胞积累增加，但其机制尚不明确。在这项研究中，我们的目的是调查微RNA调节间充质祖细胞和骨髓基质细胞（BMSC）的分化，通过调节Runx 2，骨生成的关键转录因子。我们发现miR-204及其同源物miR-211在间充质祖细胞系和BMSCs中表达，并且它们的表达在脂肪细胞分化过程中被诱导，而Runx 2蛋白表达被抑制。miR-204的逆转录病毒过表达或miR-204寡核苷酸的转染降低了Runx 2蛋白水平，并且miR-204抑制显著升高了Runx 2蛋白水平，表明miR-204在间充质祖细胞和BMSC中充当Runx 2的内源性衰减剂。推测的miR-204结合位点的突变上调Runx 2 3′-UTR报告基因活性，表明miR-204/211与Runx 2 3′-UTR结合。miR-204的干扰导致间充质祖细胞和BMSCs分化命运的改变：当miR-204在这些细胞中过表达时，成骨细胞分化受到抑制，脂肪细胞分化受到促进，而当miR-204被抑制时，成骨上调，脂肪细胞形成受到损害。总之，我们的数据表明，miR-204/211作为Runx 2的重要内源性负调控因子，其抑制间充质祖细胞和BMSC的成骨并促进脂肪生成。
Differentiation of mesenchymal stem cells into a particular lineage is tightly regulated, and malfunction of this regulation could lead to pathological consequences. Patients with osteoporosis have increased adipocyte accumulation, but the mechanisms involved remain to be defined. In this study, we aimed to investigate if micro-RNAs regulate mesenchymal progenitor cells and bone marrow stromal cell (BMSC) differentiation through modulation of Runx2, a key transcription factor for osteogenesis. We found that miR-204 and its homolog miR-211 were expressed in mesenchymal progenitor cell lines and BMSCs and their expression was induced during adipocyte differentiation, whereas Runx2 protein expression was suppressed. Retroviral overexpression of miR-204 or transfection of miR-204 oligo decreased Runx2 protein levels and miR-204 inhibition significantly elevated Runx2 protein levels, suggesting that miR-204 acts as an endogenous attenuator of Runx2 in mesenchymal progenitor cells and BMSCs. Mutations of putative miR-204 binding sites upregulated the Runx2 3′-UTR reporter activity, suggesting that miR-204/211 bind to Runx2 3′-UTR. Perturbation of miR-204 resulted in altered differentiation fate of mesenchymal progenitor cells and BMSCs: osteoblast differentiation was inhibited and adipocyte differentiation was promoted when miR-204 was overexpressed in these cells, whereasosteogenesis was upregulated and adipocyte formation was impaired when miR-204 was inhibited. Together, our data demonstrated that miR-204/211 act as important endogenous negative regulators of Runx2, which inhibit osteogenesis and promote adipogenesis of mesenchymal progenitor cells and BMSCs.
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DOI：
10.1073/pnas.0602831103
发表时间：
2006-06-06
影响因子：
11.1
作者：
Rao, Prakash K.;Kumar, Roshan M.;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
6.2
作者：
Qiu, Weimin;Andersen, Tom E.;Kassem, Moustapha
通讯作者：
Kassem, Moustapha
影响因子：
4
作者：
Takazawa, Y;Tsuji, K;Noda, M
通讯作者：
Noda, M