Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
Cell Metab. 2010 Feb 3;11(2):136-46. doi: 10.1016/j.cmet.2009.12.009.
Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, FoxO3, and FoxO4 in 3-month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis and increased osteoblast number, bone formation rate, and vertebral bone mass. We conclude that FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass homeostasis.
衰老会增加氧化应激和成骨细胞凋亡，减少骨量，而叉头框 O (FoxO) 转录因子通过激活涉及自由基清除和凋亡的基因来抵御氧化应激。在 3 个月大的小鼠中条件性删除 FoxO1、FoxO3 和 FoxO4 会导致骨内氧化应激增加、成骨细胞凋亡增加和骨细胞数量减少、骨形成率降低以及松质骨和皮质骨部位的骨量减少。删除对成骨细胞凋亡的影响是细胞自主性的，源自氧化应激。相反，成熟成骨细胞中 FoxO3 转基因的过表达会降低氧化应激和成骨细胞凋亡，增加成骨细胞数量、骨形成率和椎骨骨量。我们的结论是，FoxO 依赖性的氧化防御提供了一种机制来处理成骨细胞有氧代谢不断产生的氧自由基，因此对于骨量稳态是必不可少的。
