Department of Medicine, Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
J Bone Miner Res. 2011 May;26(5):912-7. doi: 10.1002/jbmr.306.
The FoxO family of forkhead transcription factors is at the crossroads of many signal transduction pathways that are evolutionarily conserved. Such pathways have been co-opted in differentiated tissues for a variety of vital and specialized functions, such as differentiation, proliferation, and survival in cells as diverse as adipocytes, hepatocytes, β-cells, myoblasts, thymocytes, and cancer cells. FoxO metabolic functions are relevant to glucose metabolism, tumor suppression, hematopoiesis, angiogenesis, and antioxidant defense. Among the FoxO isoforms, FoxO1 is a main target of insulin signaling and regulates metabolic homeostasis and organismal survival at many different levels. FoxO1 entered into the field of skeletal biology by a property that is unique among its functions in other organs. With the osteoblast as its target cell, FoxO1 not only acts on it to regulate bone homeostasis but also through it as a transcriptional modulator of the endocrine function of the skeleton in regulating glucose metabolism. Through its direct skeletal actions, FoxO1 promotes osteoblast proliferation by maintaining protein synthesis and redox balance. Through its endocrine actions on target tissues of insulin, FoxO1 acts by way of osteocalcin to suppress glucose production by pancreatic beta cells and hepatocytes and to decrease insulin production and sensitivity. These two parallel but opposing actions, one in favor of the skeleton and the other in disadvantage of glucose-regulating tissues, may signify an adaptive mechanism that integrates responses between different organs and is beneficial for whole-body physiology during stress and aging.
FoxO 家族的叉头转录因子位于许多信号转导途径的交汇点，这些途径在进化上是保守的。这些途径在分化组织中被用于各种重要和专门的功能，如脂肪细胞、肝细胞、β 细胞、成肌细胞、胸腺细胞和癌细胞等不同细胞的分化、增殖和存活。FoxO 的代谢功能与葡萄糖代谢、肿瘤抑制、造血、血管生成和抗氧化防御有关。在 FoxO 同工型中，FoxO1 是胰岛素信号的主要靶标，可在许多不同水平上调节代谢稳态和生物体的存活。FoxO1 通过其在其他器官的功能中独一无二的特性进入了骨骼生物学领域。以成骨细胞为靶细胞，FoxO1 不仅作用于它来调节骨稳态，而且还通过它作为骨骼内分泌功能的转录调节剂来调节葡萄糖代谢。通过其对胰岛素靶组织的直接骨骼作用，FoxO1 通过维持蛋白质合成和氧化还原平衡来促进成骨细胞增殖。通过其对胰腺β 细胞和肝细胞的胰岛素靶组织的内分泌作用，FoxO1 通过骨钙蛋白发挥作用，抑制葡萄糖的产生，并降低胰岛素的产生和敏感性。这两种平行但相反的作用，一种有利于骨骼，另一种不利于调节葡萄糖的组织，可能标志着一种适应机制，它整合了不同器官之间的反应，有利于应激和衰老期间的全身生理学。
