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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 10

The miR-2861 mutation represses miRNA expression and attenuates miRNA-mediated translational suppression.

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The miR-2861 mutation represses miRNA expression and attenuates miRNA-me...
(A) The stem-loop structures of pre–miR-C and pre–miR-G, as predicted by mfold. Mature miRNAs are highlighted in red, and the mutated nucleotide is highlighted in green (and indicated by arrows). The free energy (ΔG) calculated by mfold is indicated. (B) The C-G mutation in the stem of pre–miR-2861 inhibited mature miR-2861 expression. Human 293 cells were transfected with pcDNA3-miR-2861-C, pcDNA3-miR-2861-G, or empty vector. The cells were harvested 48 hours after transfection, and miR-2861 expression was determined by Northern blotting. U6 was used as a loading control. (C) The miR-2861 mutation attenuated miRNA-mediated translational suppression. 293 cells were cotransfected with the luciferase reporter carrying HDAC5 CDS and pcDNA3-miR-2861-C, pcDNA3-miR-2861-G, or miR-C. Effects of the WT, MUT pre–miR-2861, or control on the reporter constructs were determined 48 hours after transfection. Firefly luciferase values, normalized for Renilla luciferase, are presented. Data are shown as means ± SD. *P < 0.05 vs. control, n = 3. (D) HDAC5 and Runx2 protein levels in human bone. HDAC5 and Runx2 protein expression levels were determined by Western blotting with proteins extracted from bone of patients and controls and normalized to total protein. β-Actin was used as a loading control. Representative results are presented.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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