title: Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor.
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.
authors.affiliation: Department of Medicine, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Cohen-Kfir
authors.forename: Hanna
authors.initials: H
authors.lastname: Artsi
authors.forename: Avi
authors.initials: A
authors.lastname: Levin
authors.forename: Eva
authors.initials: E
authors.lastname: Abramowitz
authors.forename: Alon
authors.initials: A
authors.lastname: Bajayo
authors.forename: Irina
authors.initials: I
authors.lastname: Gurt
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Agustina
authors.initials: A
authors.lastname: D'Urso
authors.forename: Debra
authors.initials: D
authors.lastname: Toiber
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Rivka
authors.initials: R
authors.lastname: Dresner-Pollak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015519:Bone Density; D001853:Bone Marrow; D005260:Female; D005786:Gene Expression Regulation; D018095:Germ-Line Mutation; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D036341:Intercellular Signaling Peptides and Proteins; D059630:Mesenchymal Stem Cells; D051379:Mice; D010012:Osteogenesis; D010024:Osteoporosis; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1