FoxO1 expression in osteoblasts modulates bone formation through resistance to oxidative stress in mice
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Chengdu (China)
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan (China)
Accumulation of reactive oxygen species (ROS) induced by oxidative stress (OS) affects cell survival, cell function and even results in cell death. As a major transcription factor of forkhead O (FoxOs) family, FoxO1 orchestrates multiple osteoblastic biological processes, thus regulating osteoblast physiology and bone metabolism. However, the outcome of osteoblast behaviors varies under different physiological and pathological conditions. Also, the underlying impact of FoxO1 on oxidative stress and further on bone metabolism still remains unclear. In this study, using osteoblast-specific FoxO1 knockout (FoxO1{sub OB}{sup -/-}) mice, we investigated the potential roles of FoxO1 on bone formation and osteoblast bioactivity under physiological condition. We show herein that FoxO1-knockout decreased bone volume and bone formation rate in FoxO1{sub OB}{sup -/-} mice, which might be related to the decreased osteoblasts number. We also found that FoxO1-knockout increased apoptosis-related caspase-3 activity of osteoblasts, and inhibited the expression of osteogenic phenotypic markers (i.e. Runx2, Osx, ALP and OPN), leading to reduced osteoblasts differentiation. The alterations of bone formation and osteoblasts bioactivity were further testified to be linked to the elevated intracellular oxidative stress levels in FoxO1-deficient osteoblasts. Besides, administration of the antioxidant N-acetyl-l-cysteine (NAC) normalized the increased ROS levels in FoxO1-deficient osteoblasts, restoring the decreased osteoblasts differentiation, suppressing apoptosis-related caspase-3 activity, and promoting the expression of osteogenic markers in FoxO1-deficient osteoblasts. These results together illustrated that as a major regulator in redox homeostasis and osteoblast physiology, FoxO1 provides a favorable intracellular environment for osteoblast functions by defensing against the adverse effects of oxidative stress.
- OSTI ID:
- 23134345
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 3; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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