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In this study, we explore whether FoxO3 regulates age-related bone loss and marrow fat accumulation. The expression levels of FoxO3 in BMSCs during aging were detected in vivo and in vitro. To explore the role of FoxO3 in osteogenic and adipogenic differentiation, primary BMSCs were isolated from young and aged mice. FoxO3 expression was modulated by adenoviral vector transfection. The role of FoxO3 in bone\u2013fat balance was evaluated by alizarin red S staining, oil red O staining, quantitative reverse transcription\u2013polymerase chain reaction, Western blot, and histological analysis. Age-related bone loss and fat deposit are associated with downregulation of FoxO3. Overexpression of FoxO3 alleviated age-related bone loss and marrow fat accumulation in aged mice. Mechanistically, FoxO3 reduced adipogenesis and enhanced osteogenesis of BMSCs via downregulation of PPAR-\u03b3 and Notch signaling, respectively. In conclusion, FoxO3 is an essential factor controlling the fate of BMSCs and is a potential target for the prevention of age-related osteoporosis.<\/jats:p>","DOI":"10.1089\/scd.2024.0055","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T09:44:58Z","timestamp":1714038298000},"page":"365-375","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["FoxO3 Regulates Mouse Bone Mesenchymal Stem Cell Fate and Bone\u2013Fat Balance During Skeletal Aging"],"prefix":"10.1177","volume":"33","author":[{"given":"Wei","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Ji","family":"Tong","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 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