Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor

Endocrinology. 2011 Dec;152(12):4514-24. doi: 10.1210/en.2011-1128. Epub 2011 Sep 27.

Abstract

Sirt1, the mammalian ortholog of the yeast Sir2 (silent information regulator 2), was shown to play an important role in metabolism and in age-associated diseases, but its role in skeletal homeostasis and osteoporosis has yet not been studied. Using 129/Sv mice with a germline mutation in the Sirt1 gene, we demonstrate that Sirt1 haplo-insufficient (Sirt1(+/-)) female mice exhibit a significant reduction in bone mass characterized by decreased bone formation and increased marrow adipogenesis. Importantly, we identify Sost, encoding for sclerostin, a critical inhibitor of bone formation, as a novel target of Sirt1. Using chromatin immunoprecipitation analysis, we reveal that Sirt1 directly and negatively regulates Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter. Sost down-regulation by small interfering RNA and the administration of a sclerostin-neutralizing antibody restore gene expression of osteocalcin and bone sialoprotein as well as mineralized nodule formation in Sirt1(+/-) marrow-derived mesenchymal stem cells induced to osteogenesis. These findings reveal a novel role for Sirt1 in bone as a regulator of bone mass and a repressor of sclerostin, and have potential implications suggesting that Sirt1 is a target for promoting bone formation as an anabolic approach for treatment of osteoporosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Bone Density*
  • Bone Marrow
  • Female
  • Gene Expression Regulation
  • Germ-Line Mutation
  • Glycoproteins / antagonists & inhibitors*
  • Intercellular Signaling Peptides and Proteins
  • Mesenchymal Stem Cells
  • Mice
  • Osteogenesis*
  • Osteoporosis
  • Sirtuin 1 / genetics
  • Sirtuin 1 / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Sost protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1