Bone . 2018 Jun;111:82-91. doi: 10.1016/j.bone.2018.03.017. Epub 2018 Mar 16.

Overexpression of DNMT1 leads to hypermethylation of H19 promoter and inhibition of Erk signaling pathway in disuse osteoporosis

Bing Li  1 Jie Zhao  2 Jian-Xiong Ma  3 Guo-Min Li  4 Yang Zhang  3 Guo-Sheng Xing  3 Jun Liu  5 Xin-Long Ma  6

Affiliations

  • 1 Joint Department, Tianjin Hospital, Tianjin 300211, People’s Republic of China.
  • 2 Orthopedic Department, Tianjin Hospital, Tianjin 300211, People’s Republic of China.
  • 3 Orthopedic Research Institute, Tianjin Hospital, Tianjin 300050, People’s Republic of China.
  • 4 Graduate School, Tianjin Medical University, Tianjin 300070, People’s Republic of China.
  • 5 Joint Department, Tianjin Hospital, Tianjin 300211, People’s Republic of China. Electronic address: drliujun@hotmail.com.
  • 6 Joint Department, Tianjin Hospital, Tianjin 300211, People’s Republic of China; Orthopedic Research Institute, Tianjin Hospital, Tianjin 300050, People’s Republic of China. Electronic address: maxinlong99@163.com.

Abstract

Disuse osteoporosis (DOP) is a common complication of the lack of mechanical loading. The precise mechanism underlying DOP remains unknown, although epigenetic modifications may be a major cause. Recently, cumulative research has revealed that DNA methyltransferase (DNMT) proteins can catalyze the conversion of cytosine to 5-methylcytosine (5mC), altering the epigenetic state of DNA. Here, we report that DNMT1 expression and lncRNA-H19 methylation are upregulated in the femoral tissues of DOP rats, accompanied with inhibited Erk signaling pathway. Overexpression of DNMT1 in UMR-106 cells mimics 5mC enrichment in the H19 promoter, inhibition of Erk signaling and impairment of osteogenesis, which can be rescued by 5′-aza-deoxycytidine (5′-Aza) treatment. Moreover, local intramedullary injection of Dnmt1 siRNA (siDNMT1) in Sprague-Dawley (SD) rats abrogated disuse lncRNA-H19 (H19) downregulation, Erk signaling inhibition, histopathological changes, and bone microstructure declines in the distal femur in vivo. Therefore, our data identify for the first time a new signaling cascade in DOP: mechanical unloading causes upregulation of DNMT1 and hypermethylation of H19 promoter, which subsequently leads to downregulation of lncRNA-H19 and inhibition of the ERK signaling, suggesting a new potential therapeutic target.

Keywords: DNA methylation; DNMT1; Disuse osteoporosis; Long-noncoding RNA-H19, Erk-MAPK signaling pathway.

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