Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Curr Top Dev Biol. 2018;127:149-163. doi: 10.1016/bs.ctdb.2017.10.004. Epub 2017 Dec 14.
Recent studies with murine models of cell-specific loss- or gain-of-function of FoxOs have provided novel insights into the function and signaling of these transcription factors on the skeleton. They have revealed that FoxO actions in chondrocytes are critical for normal skeletal development, and FoxO actions in cells of the osteoclast or osteoblast lineage greatly influence bone resorption and formation and, consequently, bone mass. FoxOs also act in osteoblast progenitors to inhibit Wnt signaling and bone formation. Additionally, FoxOs decrease bone resorption via direct antioxidant effects on osteoclasts and upregulation of the antiosteoclastogenic cytokine OPG in cells of the osteoblast lineage. Deacetylation of FoxOs by the NAD-dependent histone deacetylase Sirt1 in both osteoblasts and osteoclasts stimulates bone formation and inhibits bone resorption, making Sirt1 activators promising therapeutic agents for diseases of low bone mass. In this chapter, we review these advances and discuss their implications for the pathogenesis and treatment of estrogen deficiency-, Type 1 diabetes-, and age-related osteoporosis.
最近利用特定细胞缺失或获得功能的 FoxO 基因的鼠模型的研究，为这些转录因子在骨骼中的功能和信号转导提供了新的认识。研究揭示，FoxO 在软骨细胞中的作用对于骨骼的正常发育至关重要，FoxO 在破骨细胞或成骨细胞谱系细胞中的作用极大地影响了骨吸收和形成，进而影响骨量。FoxO 还在成骨细胞祖细胞中通过直接的抗氧化作用抑制 Wnt 信号转导和骨形成。此外，FoxO 通过直接的抗氧化作用抑制破骨细胞的骨吸收，并上调成骨细胞谱系细胞中的抗破骨细胞形成细胞因子 OPG。NAD 依赖性组蛋白去乙酰化酶 Sirt1 对成骨细胞和破骨细胞中 FoxO 的去乙酰化作用刺激骨形成并抑制骨吸收，这使得 Sirt1 激活剂成为治疗低骨量疾病的有前途的治疗剂。在本章中，我们将回顾这些进展，并讨论它们对雌激素缺乏、1 型糖尿病和年龄相关性骨质疏松症的发病机制和治疗的影响。
