A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans.
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.
Li
Hui
H
Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
Xie
Hui
H
Liu
Wei
W
Hu
Rong
R
Huang
Bi
B
Tan
Yan-Fei
YF
Xu
Kang
K
Sheng
Zhi-Feng
ZF
Zhou
Hou-De
HD
Wu
Xian-Ping
XP
Luo
Xiang-Hang
XH
D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D017124:Conserved Sequence; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D005260:Female; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology*; D010024:Osteoporosis / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D010375:Pedigree
D050659:Core Binding Factor Alpha 1 Subunit; D035683:MicroRNAs; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; C404500:HDAC5 protein, human; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases