A microRNA signature for a BMP2-induced osteoblast lineage commitment program
A microRNA signature for a BMP2-induced osteoblast lineage commitment program
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DOI：
10.1073/pnas.0804438105
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发表时间：
2008-09-16
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：
Li, Zhaoyong;Hassan, Mohammad Q.;Stein, Gary S.
骨形态发生蛋白 (BMP) 是有效的形态发生素，可激活谱系决定的转录程序。 BMP 对表型的诱导如何与抑制生物途径以控制细胞分化的 microRNA (miRNA) 相协调仍不清楚。在这里，我们通过分析 BMP2 诱导 C2C12 间充质细胞成骨过程中的 miRNA，发现响应 BMP2 而显着变化的 25 个 miRNA 中有 22 个被下调。这些 miRNA 预计会靶向多种成骨途径的成分。我们表征了两个代表性的 miRNA，并表明 miR-133 直接靶向 Runx2（一种对骨形成至关重要的早期 BMP 反应基因），而 miR-135 靶向 Smad5（BMP2 成骨信号的关键传感器），通过其 3'UTR 序列控制。两种 miRNA 均通过减弱 Runx2 和 Smad5 通路（协同促进骨形成）来抑制骨祖细胞的分化。尽管已知 miR-133 可以促进 MEF-2 依赖性肌生成，但我们已经确定了第二种互补功能来抑制 Runx2 介导的成骨。我们的主要发现是，BMP2 通过诱导靶向肌肉基因的 miRNA 来控制骨细胞决定，但主要是通过下调构成成骨程序的多个 miRNA，从而从抑制途径中释放细胞谱系定型所需的成分。因此，我们的研究建立了 BMP 形态发生素选择性诱导组织特异性表型并抑制替代谱系的机制。
Bone morphogenetic proteins (BMPs) are potent morphogens that activate transcriptional programs for lineage determination. How BMP induction of a phenotype is coordinated with microRNAs (miRNAs) that inhibit biological pathways to control cell differentiation, remains unknown. Here, we show by profiling miRNAs during BMP2 induced osteogenesis of C2C12 mesenchymal cells, that 22 of 25 miRNAs which significantly changed in response to BMP2 are down-regulated. These miRNAs are each predicted to target components of multiple osteogenic pathways. We characterize two representative miRNAs and show that miR-133 directly targets Runx2, an early BMP response gene essential for bone formation, and miR-135 targets Smad5, a key transducer of the BMP2 osteogenic signal, controlled through their 3'UTR sequences. Both miRNAs functionally inhibit differentiation of osteoprogenitors by attenuating Runx2 and Smad5 pathways that synergistically contribute to bone formation. Although miR-133 is known to promote MEF-2-dependent myogenesis, we have identified a second complementary function to inhibit Runx2-mediated osteogenesis. Our key finding is that BMP2 controls bone cell determination by inducing miRNAs that target muscle genes but mainly by down-regulating multiple miRNAs that constitute an osteogenic program, thereby releasing from inhibition pathway components required for cell lineage commitment. Thus, our studies establish a mechanism for BMP morphogens to selectively induce a tissue-specific phenotype and suppress alternative lineages.