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Transforming Growth Factor β1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression

  • Zhao, Hongying (Department of Pharmacy, Zhejiang Provincial People's Hospital) ;
  • Zhang, Jun (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Shao, Haiyu (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Liu, Jianwen (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Jin, Mengran (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Chen, Jinping (Department of Orthopedics, Zhejiang Provincial People's Hospital) ;
  • Huang, Yazeng (Department of Orthopedics, Zhejiang Provincial People's Hospital)
  • Received : 2016.12.12
  • Accepted : 2017.02.22
  • Published : 2017.03.31

Abstract

Transforming growth factor ${\beta}1$ $(TGF{\beta}1)/Smad4$ 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 $TGF{\beta}1/Smad4$ signaling. Here, we present that $TGF{\beta}1$ 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 $TGF{\beta}1$. The results of luciferase reporter experiments and ChIP assays demonstrated that $TGF{\beta}1$ promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the $TGF{\beta}1/Smad4$ pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the $TGF{\beta}1$-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 $TGF{\beta}1/Smad4$ 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.

Keywords

miR-155;osteoclast differentiation;Smad4;$TGF{\beta}1$

Acknowledgement

Supported by : Natural Science Foundation of China, Natural Scientific Research Foundation of Zhejiang Medical College, Zhejiang Provincial Health Bureau Science Foundation of China, Zhejiang Provincial Chinese Traditional Medicine Bureau Science Foundation of China

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