A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2
A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2
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DOI：
10.1073/pnas.1018493108
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发表时间：
2011-06-14
影响因子：
11.1
通讯作者：
Stein, Gary S.
中科院分区：
文献类型：
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作者：
Zhang, Ying;Xie, Rong-lin;Stein, Gary S.
成骨细胞和软骨细胞的谱系进展受到细胞命运决定转录因子 Runx2 的严格控制。在本研究中，我们直接探讨了 microRNA (miRNA) 是否可以控制 Runx2 的成骨活性并影响成骨细胞成熟。一组 11 个 Runx2 靶向 miRNA（miR-23a、miR-30c、miR-34c、miR-133a、miR-135a、miR-137、miR-204、miR-205、miR-217、miR-218 和 miR-338）在间充质细胞类型中以谱系相关模式表达。在成骨和软骨分化过程中，这些 miRNA 通常相对于 Runx2 呈反向表达。基于 3'UTR 荧光素酶报告基因、免疫印迹和 mRNA 稳定性测定，每种 miRNA 都会直接减弱 Runx2 蛋白的积累。靶向 Runx2 的 miRNA 差异性地抑制成骨细胞和软骨细胞中 Runx2 蛋白的表达，并表现出不同的功效。因此，细胞环境有助于 miRNA 介导的 Runx2 调节。所有针对 Runx2 的 miRNA（除 miR-218 外）均显着阻碍成骨细胞分化，并且其作用可以通过相应的抗 miRNA 逆转。这些发现表明，成骨细胞生成受到功能测试 miRNA 的复杂网络的限制，这些 miRNA 直接针对成骨主调节因子 Runx2。
Lineage progression in osteoblasts and chondrocytes is stringently controlled by the cell-fate-determining transcription factor Runx2. In this study, we directly addressed whether microRNAs (miRNAs) can control the osteogenic activity of Runx2 and affect osteoblast maturation. A panel of 11 Runx2-targeting miRNAs (miR-23a, miR-30c, miR-34c, miR-133a, miR-135a, miR-137, miR-204, miR-205, miR-217, miR-218, and miR-338) is expressed in a lineage-related pattern in mesenchymal cell types. During both osteogenic and chondrogenic differentiation, these miRNAs, in general, are inversely expressed relative to Runx2. Based on 3'UTR luciferase reporter, immunoblot, and mRNA stability assays, each miRNA directly attenuates Runx2 protein accumulation. Runx2-targeting miRNAs differentially inhibit Runx2 protein expression in osteoblasts and chondrocytes and display different efficacies. Thus, cellular context contributes to miRNA-mediated regulation of Runx2. All Runx2-targeting miRNAs (except miR-218) significantly impede osteoblast differentiation, and their effects can be reversed by the corresponding anti-miRNAs. These findings demonstrate that osteoblastogenesis is limited by an elaborate network of functionally tested miRNAs that directly target the osteogenic master regulator Runx2.