miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation.
miR-542-3p suppresses osteoblast cell proliferation and differentiation, targets BMP-7 signaling and inhibits bone formation.
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DOI：
10.1038/cddis.2014.4
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发表时间：
2014-02-06
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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MicroRNAs （miRNAs）是一种短的非编码rna，可以干扰特定靶mrna的翻译，从而调节多种生物过程。最近的研究表明，mirna可能在成骨细胞分化和骨形成中起作用。在这里，我们发现miR-542-3p是一种特征明确的肿瘤抑制因子，其下调通过c- src相关的致癌途径与肿瘤进展密切相关，抑制成骨细胞的增殖和分化。在Medicarpin（一种已证实具有成骨作用的翼龙木）诱导的小鼠颅骨成骨细胞中进行miRNA阵列分析，并通过定量实时PCR进一步验证，发现miR-542-3p在成骨细胞分化过程中下调。过表达miR-542-3p抑制成骨细胞分化，而通过抗miR-542-3p抑制miR-542-3p功能促进成骨细胞特异性基因的表达、碱性磷酸酶活性和基质矿化。靶标预测分析工具和荧光素酶3 ' UTR报告基因检测的实验验证发现BMP-7（骨形态发生蛋白7）是miR-542-3p的直接靶标。我们发现，过表达miR-542-3p导致BMP-7的抑制和BMP-7/PI3K- survivin信号的抑制。这强烈提示miR-542-3p通过抑制BMP-7及其下游信号通路抑制成骨分化，促进成骨细胞凋亡。此外，miR-542-3p的沉默导致假手术和卵巢切除（Ovx）小鼠骨形成、骨强度增加和小梁微结构改善。虽然已知miR-542-3p是一种肿瘤抑制因子，但我们已经确定了miR-542-3p的第二种互补功能，即它抑制bmp -7介导的成骨。我们的研究结果表明，抗miR-542-3p对miR-542-3p的药理学抑制可能代表了一种促进体内骨形成的治疗策略。
MicroRNAs (miRNAs) are short non-coding RNAs that interfere with translation of specific target mRNAs and thereby regulate diverse biological processes. Recent studies have suggested that miRNAs might have a role in osteoblast differentiation and bone formation. Here, we show that miR-542-3p, a well-characterized tumor suppressor whose downregulation is tightly associated with tumor progression via C-src-related oncogenic pathways, inhibits osteoblast proliferation and differentiation. miRNA array profiling in Medicarpin (a pterocarpan with proven bone-forming effects) induced mice calvarial osteoblast cells and further validation by quantitative real-time PCR revealed that miR-542-3p was downregulated during osteoblast differentiation. Over-expression of miR-542-3p inhibited osteoblast differentiation, whereas inhibition of miR-542-3p function by anti-miR-542-3p promoted expression of osteoblast-specific genes, alkaline phosphatase activity and matrix mineralization. Target prediction analysis tools and experimental validation by luciferase 3′ UTR reporter assay identified BMP-7 (bone morphogenetic protein 7) as a direct target of miR-542-3p. It was seen that over-expression of miR-542-3p leads to repression of BMP-7 and inhibition of BMP-7/PI3K- survivin signaling. This strongly suggests that miR-542-3p suppresses osteogenic differentiation and promotes osteoblast apoptosis by repressing BMP-7 and its downstream signaling. Furthermore, silencing of miR-542-3p led to increased bone formation, bone strength and improved trabecular microarchitecture in sham and ovariectomized (Ovx) mice. Although miR-542-3p is known to be a tumor repressor, we have identified second complementary function of miR-542-3p where it inhibits BMP-7-mediated osteogenesis. Our findings suggest that pharmacological inhibition of miR-542-3p by anti-miR-542-3p could represent a therapeutic strategy for enhancing bone formation in vivo.
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作者：
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通讯作者：
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DOI：
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