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FOXO1 differentially regulates bone formation in young and aged mice
Yi Xiong1, Yixin Zhang2, Feng Zhou2
1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China; Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Cellular Signalling
|August 18, 2022
Summary
FOXO1 deletion causes bone loss in young mice but improves bone healing in aged mice by modulating oxidative stress and Wnt/β-catenin signaling. This offers new osteoporosis treatment strategies.
Area of Science:
- Bone Biology
- Molecular Mechanisms of Aging
- Transcription Factor Function
Background:
- Osteoporosis and fracture healing present significant challenges, particularly in aging populations.
- FOXO1, a key transcription factor, plays a critical role in cellular processes including oxidative stress resistance and metabolism.
- Previous studies indicated differential effects of osteoblast-specific Foxo1 deletion on bone in young versus aged mice, necessitating mechanistic investigation.
Purpose of the Study:
- To elucidate the mechanism behind FOXO1's differential regulation of bone metabolism in young and aged mice.
- To investigate the role of oxidative stress and Wnt/β-catenin signaling in FOXO1-mediated bone effects.
- To explore FOXO1 as a potential therapeutic target for age-related osteoporosis and impaired fracture healing.
Main Methods:
- Generation of osteoblast-specific Foxo1 knockout mice using Foxo1fl/fl and Bglap-Cre models.
- Assessment of bone formation rate, osteoblast differentiation, and bone defect healing in young and aged knockout mice.
- Analysis of the interplay between FOXO1, reactive oxygen species (ROS), and Wnt/β-catenin signaling.
Main Results:
- In young mice, Foxo1 deletion impaired osteoblast differentiation and bone formation due to reduced oxidative stress resistance, leading to bone loss and delayed healing.
- In aged mice, FOXO1 deficiency promoted Wnt/β-catenin signaling by preventing β-catenin diversion from TCF4, thereby improving osteogenic activity and bone healing.
- High ROS levels in aged mice shift β-catenin binding from TCF4 to FOXO1, inhibiting Wnt/β-catenin signaling and osteogenesis.
Conclusions:
- FOXO1 exhibits age-dependent, differential effects on bone metabolism.
- FOXO1 deficiency ameliorates age-related bone loss and enhances fracture healing by reactivating Wnt/β-catenin signaling.
- Targeting FOXO1 offers a novel therapeutic avenue for treating age-related osteoporosis and improving fracture repair.
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