FOXO1 differentially regulates bone formation in young and aged mice

It is a great challenge to develop a safe and effective treatment strategy for age-related osteoporosis and fracture healing. As one of the four FOXO transcription factors, FOXO1 is essential for cell proliferation, survival, senescence, energy metabolism, and oxidative stress in various cells. Our previous study demonstrated that specific Foxo1 gene deletion in osteoblasts in young mice results in bone loss while that in aged mice shows the opposite effect. However, the mechanism underlying the differential regulation of bone metabolism by FOXO1 remains to be elucidated. In this study, we generated osteoblast-specific Foxo1 knockout mice by using Foxo1fl/fl and Bglap-Cre mice. In young mice, Foxo1 gene deletion inhibits osteoblast differentiation, leading to a decreased osteoblast number and decreased bone formation rate because of the weakened ability to resist oxidative stress, eventually resulting in bone loss and delayed healing of bone defects. In aged mice, high levels of reactive oxygen species (ROS) promote the diversion of CTNNB1 (β-catenin) from T cell factor 4 (TCF4)- to FOXO1-mediated transcription, thereby inhibiting Wnt/β-catenin signaling and leading to decreased osteogenic activity. Conversely, FOXO1 deficiency indirectly promotes the binding of β-catenin and TCF4 and activates Wnt/β-catenin signaling, thereby alleviating age-related bone loss and improving bone defect healing. Our study proves that FOXO1 has differential effects on bone metabolism in young and aged mice and elucidates its underlying mechanism. Further, this study provides a new perspective on the treatment of age-related osteoporosis.