A microRNA expression signature of osteoclastogenesis
A microRNA expression signature of osteoclastogenesis
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DOI：
10.1182/blood-2010-10-311415
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发表时间：
2011-03-31
期刊：
影响因子：
20.3
通讯作者：
Hruska, Keith A.
中科院分区：
文献类型：
--
作者：
Sugatani, Toshifumi;Vacher, Jean;Hruska, Keith A.
MicroRNAs(MiRs)是一种小的非编码RNA，主要在动物细胞中蛋白质翻译的时空调节中发挥作用。虽然新出现的证据表明，一些MIR在成骨细胞形成和骨骼动态平衡中发挥重要作用，但对破骨细胞形成的了解要少得多。在这里，我们发现核因子kappa B受体激活剂(RANKL)诱导的破骨细胞生成是由miR-21介导的。MIR-21被认为是RANKL诱导的破骨细胞生成的miR表达信号，它下调了程序性细胞死亡4(PDCD4)的蛋白水平。减弱的PDCD4消除了c-Fos的抑制作用，c-Fos是破骨细胞发生和破骨细胞特异性下游靶基因的关键转录因子。此外，RANKL诱导的c-Fos上调miR-21基因表达。缺乏与miR生物发生相关的RNA结合蛋白DiGeorge综合征临界区基因8和与miR生物发生相关的RNaseIII家族的内切核酸酶DICER的骨髓来源的单核/巨噬细胞前体细胞具有显著的miR-21水平降低和PDCD4蛋白水平升高，从而阻碍了RANKL诱导的破骨细胞形成。然而，强制表达miR-21挽救了破骨细胞的发育，因为PDCD4蛋白表达水平下调。因此，我们的研究提供了一个新的分子机制，包括c-Fos/miR-21/PDCD4的正反馈回路，调节破骨细胞的发生。(血。2011；117(13)：3648-3657)
MicroRNAs (miRs) are small noncoding RNAs that principally function in the spatiotemporal regulation of protein translation in animal cells. Although emerging evidence suggests that some miRs play important roles in osteoblastogenesis and skeletal homeostasis, much less is known in osteoclastogenesis. Here, we show that receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis is mediated by miR-21. MiR-21 was identified as an miR expression signature of RANKL-induced osteoclastogenesis that down-regulates programmed cell death 4 (PDCD4) protein levels. Diminished PDCD4 removes a repression from c-Fos, a critical transcription factor for osteoclasto-genesis and osteoclast-specific down stream target genes. In addition, RANKL-induced c-Fos up-regulates miR-21 gene expression. Bone marrow-derived monocyte/macrophage precursors deficient of DiGeorge syndrome critical region gene 8, an RNA binding protein associated with miR biogenesis, and Dicer, an endoribonuclease in the RNaseIII family associated with miR biogenesis, possessed significantly decreased miR-21 levels and increased PDCD4 protein levels so that RANKL-induced osteoclastogenesis was impaired in those cells. However, forced expression of miR-21 rescued osteoclast development because of down-regulation of PDCD4 protein expression levels. Thus, our studies provide a new molecular mechanism, including a positive feedback loop of c-Fos/miR-21/PDCD4, regulating osteoclastogenesis. (Blood. 2011;117(13):3648-3657)