title: miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1.
abstract: Uncontrolled oxidative stress impairs bone formation and induces age-related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR-182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR-182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, whereas in vivo overexpression of miR-182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR-182, and restoration of FoxO1 expression in miR-182-overexpressing osteoblasts rescued them from the inhibitory effects of miR-182. These results indicate that miR-182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR-182 could be of therapeutic value.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyoung Min
authors.initials: KM
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Gadi
authors.initials: G
authors.lastname: Jogeswar
authors.forename: Jami
authors.initials: J
authors.lastname: Ajita
authors.forename: Yumie
authors.initials: Y
authors.lastname: Rhee
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Sung-Kil
authors.initials: SK
authors.lastname: Lim
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D023421:Models, Animal; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D012886:Skull / Q000166:cytology; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C576353:MIRN182 microRNA, zebrafish; D035683:MicroRNAs; C540524:Mirn182 microRNA, mouse; D029961:Zebrafish Proteins; C576354:foxo1a protein, zebrafish