title: Sirtuin1 (Sirt1) promotes cortical bone formation by preventing β-catenin sequestration by FoxO transcription factors in osteoblast progenitors.
abstract: A decline of the levels and activity of Sirtuin1 (Sirt1), a NAD(+) class III histone deacetylase, with age contributes to the development of several diseases including type 2 diabetes, neurodegeneration, inflammation, and cancer. The anti-aging effects of Sirt1 evidently result from the deacetylation of many transcription factors and co-factors including members of the Forkhead box O (FoxO) family and β-catenin. Wnt/β-catenin is indispensable for osteoblast generation. FoxOs, on the other hand, sequester β-catenin and inhibit osteoprogenitor proliferation. Here, we have deleted Sirt1 in osteoprogenitors expressing Osterix1 (Osx1)-Cre and their descendants. Sirt1(ΔOsx1) mice had lower cortical thickness in femora and vertebrae because of reduced bone formation at the endocortical surface. In line with this, osteoprogenitor cell cultures from the Sirt1(ΔOsx1) mice exhibited lower alkaline phosphatase activity and mineralization, as well as decreased proliferation and increased apoptosis. These changes were associated with decreased Wnt/β-catenin signaling and expression of cyclin D1 and resulted from increased binding of FoxOs to β-catenin. These findings demonstrate that Sirt1-induced deacetylation of FoxOs unleashes Wnt signaling. A decline in Sirt1 activity in osteoblast progenitors with aging may, therefore, contribute to the age-related loss of bone mass. Together with evidence that Sirt1 activators increase bone mass in aged mice, our results also suggest that Sirt1 could be a therapeutic target for osteoporosis.
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Srividhya
authors.initials: S
authors.lastname: Iyer
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Shoshana M
authors.initials: SM
authors.lastname: Bartell
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Ha-Neui
authors.initials: HN
authors.lastname: Kim
authors.affiliation: the Division of Pulmonary and Critical Care, the University of Arkansas for Medical Sciences and.
authors.forename: Igor
authors.initials: I
authors.lastname: Gubrij
authors.affiliation: the Translational Gerontology Branch, NIA, National Institutes of Health, Baltimore, Maryland 21224 the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205 and.
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and schullermaria@uams.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
mesh_terms: D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D017931:DNA Primers; D051858:Forkhead Transcription Factors / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D051858:Forkhead Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Animal Model; Apoptosis; Cell Proliferation; Osteoporosis; Wnt Signaling