FoxO1 is a Positive Regulator of Bone Formation by Favoring Protein Synthesis and Resistance to Oxidative Stress in Osteoblasts

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2010 Feb 10

PMID 20142102

Citations 176

Authors

Marie-Therese Rached

Aruna Kode

Lili Xu

Yoshihiro Yoshikawa

Ji-Hye Paik

Ronald A DePinho

Stavroula Kousteni

Affiliations

Soon will be listed here.

Abstract

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.

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