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A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans
Hui Li, … , Xian-Ping Wu, Xiang-Hang Luo
Hui Li, … , Xian-Ping Wu, Xiang-Hang Luo
Published November 16, 2009
Citation Information: J Clin Invest. 2009;119(12):3666-3677. https://doi.org/10.1172/JCI39832.
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Research Article Bone biology Article has an altmetric score of 7

A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans

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Abstract

MicroRNAs (miRNAs) interfere with translation of specific target mRNAs and are thought to thereby regulate many cellular processes. Recent studies have suggested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify a new miRNA (miR-2861) in primary mouse osteoblasts that promotes osteoblast differentiation by repressing histone deacetylase 5 (HDAC5) expression at the post-transcriptional level. miR-2861 was found to be transcribed in ST2 stromal cells during bone morphogenetic protein 2–induced (BMP2-induced) osteogenesis, and overexpression of miR-2861 enhanced BMP2-induced osteoblastogenesis, whereas inhibition of miR-2861 expression attenuated it. HDAC5, an enhancer of runt-related transcription factor 2 (Runx2) degradation, was confirmed to be a target of miR-2861. In vivo silencing of miR-2861 in mice reduced Runx2 protein expression, inhibited bone formation, and decreased bone mass. Importantly, miR-2861 was found to be conserved in humans, and a homozygous mutation in pre–miR-2861 that blocked expression of miR-2861 was shown to cause primary osteoporosis in 2 related adolescents. Consistent with the mouse data, HDAC5 levels were increased and Runx2 levels decreased in bone samples from the 2 affected individuals. Thus, our studies show that miR-2861 plays an important physiological role in osteoblast differentiation and contributes to osteoporosis via its effect on osteoblasts.

Authors

Hui Li, Hui Xie, Wei Liu, Rong Hu, Bi Huang, Yan-Fei Tan, Er-Yuan Liao, Kang Xu, Zhi-Feng Sheng, Hou-De Zhou, Xian-Ping Wu, Xiang-Hang Luo

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Figure 3

Inhibition of miR-2861 limits BMP2-induced osteogenic differentiation.

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Inhibition of miR-2861 limits BMP2-induced osteogenic differentiation.
S...
ST2 cells were treated with BMP2 and transiently transfected with anti–miR-2861 or anti–miR-C. (A) Northern blotting showed that anti–miR-2861 repressed the expression of miR-2861 in BMP2-induced ST2 cells. (B) ALP activity and osteocalcin secretion were measured at 48 hours as described in Figure 2B. (C) Runx2 mRNA and protein expression were detected as described in Figure 2D. *P < 0.05 vs. anti–miR-C.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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