title: A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans.
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.affiliation: Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Bi
authors.initials: B
authors.lastname: Huang
authors.forename: Yan-Fei
authors.initials: YF
authors.lastname: Tan
authors.forename: Kang
authors.initials: K
authors.lastname: Xu
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Sheng
authors.forename: Hou-De
authors.initials: HD
authors.lastname: Zhou
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Wu
authors.forename: Xiang-Hang
authors.initials: XH
authors.lastname: Luo
mesh_terms: 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
chemical_list: 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