title: Transforming Growth Factor β1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression.
abstract: Transforming growth factor β1 (TGFβ1)/Smad4 signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through TGFβ1/Smad4 signaling. Here, we present that TGFβ1 elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR-155 induced by TGFβ1. The results of luciferase reporter experiments and ChIP assays demonstrated that TGFβ1 promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start sitein vivo, further verifying that miR-155 is a transcriptional target of the TGFβ1/Smad4 pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the TGFβ1-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that TGFβ1/Smad4 signaling affects osteoclast differentiation by regulation of miR-155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise.
authors.affiliation: Department of Pharmacy, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Haiyu
authors.initials: H
authors.lastname: Shao
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Mengran
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China.
authors.forename: Yazeng
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D053245:RANK Ligand / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D053245:RANK Ligand; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C508961:Tgfb1 protein, mouse; C505689:Tnfsf11 protein, mouse; D053773:Transforming Growth Factor beta1; D016173:Macrophage Colony-Stimulating Factor
keywords: Smad4; TGFβ1; miR-155; osteoclast differentiation