FoxO3 Regulates Mouse Bone Mesenchymal Stem Cell Fate and Bone-Fat Balance During Skeletal Aging

Stem Cells Dev. 2024 Jul;33(13-14):365-375. doi: 10.1089/scd.2024.0055. Epub 2024 May 13.

Abstract

Age-related osteoporosis is characterized by an imbalance between osteogenic and adipogenic differentiation in bone mesenchymal stem cells (BMSCs). Forkhead box O 3 (FoxO3) transcription factor is involved in lifespan and cell differentiation. 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-fat balance was evaluated by alizarin red S staining, oil red O staining, quantitative reverse transcription-polymerase 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-γ 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.

Keywords: FoxO3 (Forkhead box O 3); adipogenesis; aging; bone mesenchymal stem cells (BMSCs); osteogenesis; osteoporosis.

MeSH terms

  • Adipogenesis* / genetics
  • Aging* / genetics
  • Aging* / metabolism
  • Animals
  • Bone and Bones / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Forkhead Box Protein O3* / genetics
  • Forkhead Box Protein O3* / metabolism
  • Male
  • Mesenchymal Stem Cells* / cytology
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis* / genetics
  • Osteoporosis / genetics
  • Osteoporosis / metabolism
  • Osteoporosis / pathology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction

Substances

  • Forkhead Box Protein O3
  • FoxO3 protein, mouse
  • PPAR gamma
  • Receptors, Notch