Department of Medicine, Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Cell Metab. 2010 Feb 3;11(2):147-60. doi: 10.1016/j.cmet.2010.01.001.
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.
骨质疏松症是一种骨量低的疾病，与成骨细胞数量减少和氧化应激水平升高有关。由于 FoxO 家族的转录因子赋予了细胞抵抗应激的能力，我们研究了它们对骨骼完整性的潜在影响。在这里，我们采用细胞特异性缺失和分子分析的方法表明，在三种 FoxO 蛋白中，只有 FoxO1 对于成骨细胞的增殖和氧化还原平衡是必需的，从而控制着骨形成。FoxO1 通过与调节氨基酸摄取的转录因子 ATF4 相互作用以及通过调节影响 p53 信号的应激相关途径来调节成骨细胞增殖。因此，降低氧化应激水平或增加蛋白质摄入可使特异性缺乏成骨细胞 FoxO1 的小鼠的骨形成和骨量恢复正常。这些结果表明 FoxO1 是成骨细胞生理学的关键调节剂，并为氧化应激与骨重塑调节之间提供了直接的机制联系。
