SIRT6 promotes osteogenic differentiation of mesenchymal stem cells through BMP signaling

Sci Rep. 2017 Aug 31;7(1):10229. doi: 10.1038/s41598-017-10323-z.

Abstract

SIRT6 has been identified as an H3K9 deacetylase and a critical regulator of genome stability, telomere integrity, and metabolic homeostasis. Sirt6-deficient mice displayed dramatic phenotypes including profound lymphopenia, loss of subcutaneous fat, lordokyphosis and low bone marrow density. Here, we report that SIRT6 regulates osteogenic differentiation independent of its deacetylase activity in vitro. Further mechanistic studies showed that SIRT6 involves the cell fate determination by modulating bone morphogenetic protein (BMP) signaling. Unexpectedly, this modulation depends upon P300/CBP-associated factor (PCAF). In addition, we observed impaired SIRT6 expression in bone marrow mesenchymal stem cells and in bone sections of ovariectomized mice. Taken together, our present study provide new insights into mechanisms of SIRT6-regulated MSC function beyond its H3K9 deacetylase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Gene Expression Regulation
  • Histone Deacetylases / metabolism
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Osteogenesis*
  • Ovariectomy
  • Signal Transduction
  • Sirtuins / deficiency
  • Sirtuins / genetics*
  • Sirtuins / metabolism*
  • p300-CBP Transcription Factors / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Sirt6 protein, mouse
  • Sirtuins
  • Histone Deacetylases