TY - JOUR
T1 - FoxO1 Is a Positive Regulator of Bone Formation by Favoring Protein Synthesis and Resistance to Oxidative Stress in Osteoblasts
AU - Rached, Marie Therese
AU - Kode, Aruna
AU - Xu, Lili
AU - Yoshikawa, Yoshihiro
AU - Paik, Ji Hye
AU - DePinho, Ronald A.
AU - Kousteni, Stavroula
N1 - Funding Information:
The authors are grateful to Dr. Gerard Karsenty for helpful discussions, for critical reading of the manuscript, and for providing ATF4-deficient osteoblasts. We are also thankful to Dr. John P. Bilezikian and Dr. Patricia Ducy for helpful discussions, Dr. John Manavalan for help with measurements of ROS levels in osteoblasts, Dr. Li Qiang for help with the adenoviral infections, and Charles Duncan for technical assistance. We are thankful to the histology facility of the Diabetes and Endocrinology Research Center (DERC) of Columbia University Medical Center (supported by National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK] DK063608-07) for help with histological analysis. S.K. is indebted to Dr. Vijay Yadav for his generous help and constant availability throughout this project. This work was supported by the National Institutes of Health (R01 AR055931 and R01 AR054447 to S.K.).
PY - 2010/2/3
Y1 - 2010/2/3
N2 - Osteoporosis, a disease of low bone mass, is associated with decreased osteoblast numbers and increased levels of oxidative stress within osteoblasts. Since transcription factors of the FoxO family confer stress resistance, we investigated their potential impact on skeletal integrity. Here we employ cell-specific deletion and molecular analyses to show that, among the three FoxO proteins, only FoxO1 is required for proliferation and redox balance in osteoblasts and thereby controls bone formation. FoxO1 regulation of osteoblast proliferation occurs through its interaction with ATF4, a transcription factor regulating amino acid import, as well as through its regulation of a stress-dependent pathway influencing p53 signaling. Accordingly, decreasing oxidative stress levels or increasing protein intake normalizes bone formation and bone mass in mice lacking FoxO1 specifically in osteoblasts. These results identify FoxO1 as a crucial regulator of osteoblast physiology and provide a direct mechanistic link between oxidative stress and the regulation of bone remodeling.
AB - Osteoporosis, a disease of low bone mass, is associated with decreased osteoblast numbers and increased levels of oxidative stress within osteoblasts. Since transcription factors of the FoxO family confer stress resistance, we investigated their potential impact on skeletal integrity. Here we employ cell-specific deletion and molecular analyses to show that, among the three FoxO proteins, only FoxO1 is required for proliferation and redox balance in osteoblasts and thereby controls bone formation. FoxO1 regulation of osteoblast proliferation occurs through its interaction with ATF4, a transcription factor regulating amino acid import, as well as through its regulation of a stress-dependent pathway influencing p53 signaling. Accordingly, decreasing oxidative stress levels or increasing protein intake normalizes bone formation and bone mass in mice lacking FoxO1 specifically in osteoblasts. These results identify FoxO1 as a crucial regulator of osteoblast physiology and provide a direct mechanistic link between oxidative stress and the regulation of bone remodeling.
KW - HUMDISEASE
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U2 - 10.1016/j.cmet.2010.01.001
DO - 10.1016/j.cmet.2010.01.001
M3 - Article
C2 - 20142102
AN - SCOPUS:75149115329
SN - 1550-4131
VL - 11
SP - 147
EP - 160
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -