title: FOXOs attenuate bone formation by suppressing Wnt signaling.
abstract: Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
authors.forename: Srividhya
authors.initials: S
authors.lastname: Iyer
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrogini
authors.forename: Shoshana M
authors.initials: SM
authors.lastname: Bartell
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Paula K
authors.initials: PK
authors.lastname: Roberson
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
mesh_terms: D050156:Adipogenesis; D050154:Adiposity; D000818:Animals; D015519:Bone Density; D001853:Bone Marrow / Q000033:anatomy & histology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010012:Osteogenesis; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D017382:Reactive Oxygen Species; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors