Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts.
Hypoxia decreases sclerostin expression and increases Wnt signaling in osteoblasts.
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DOI：
10.1002/jcb.22559
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发表时间：
2010-05-15
影响因子：
4
通讯作者：
Yellowley, Clare E.
中科院分区：
文献类型：
--
作者：
Genetos, Damian C.;Toupadakis, Chrisoula A.;Raheja, Leah F.;Wong, Alice;Papanicolaou, Savvas E.;Fyhrie, David P.;Loots, Gabriela G.;Yellowley, Clare E.
硬化蛋白功能或表达的突变导致硬化性骨发育不良，涉及Wnt/Lrp5信号的拮抗作用降低。相反，与野生型对照相比，成骨细胞中VHL肿瘤抑制因子的缺失增加了骨矿物质含量和横截面积，从而稳定了HIF-α亚型，从而使HIF-α/β驱动的基因转录成为可能。我们检测了细胞缺氧（1%氧）对硬化蛋白表达和典型Wnt信号传导的影响。缺氧培养的成骨细胞和骨细胞显示出硬化蛋白转录物和蛋白水平降低，活化β-连环蛋白的表达和核定位增加。同样，缺氧和模拟缺氧的DFO都增加了β-连环蛋白基因报告活性。缺氧及其模拟物增加BMP拮抗剂gremlin和noggin的表达，降低Smad-1/5/8磷酸化。作为氧对硬化蛋白调控机制的部分解释，MEF2报告基因检测显示其活性降低。正常或缺氧条件下VEGF信号的调节对Sost转录没有影响。这些数据表明，缺氧通过增强对BMP信号的拮抗作用抑制硬化蛋白的表达，而不依赖于VEGF。j .细胞。生物化学学报，2010,31(2):457-467。
Mutations in sclerostin function or expression cause sclerosing bone dysplasias, involving decreased antagonism of Wnt/Lrp5 signaling. Conversely, deletion of the VHL tumor suppressor in osteoblasts, which stabilize HIF-α isoforms and thereby enables HIF-α/β-driven gene transcription, increases bone mineral content and cross-sectional area compared to wild-type controls. We examined the influence of cellular hypoxia (1% oxygen) upon sclerostin expression and canonical Wnt signaling. Osteoblasts and osteocytes cultured under hypoxia revealed decreased sclerostin transcript and protein, and increased expression and nuclear localization of activated β-catenin. Similarly, both hypoxia and the hypoxia mimetic DFO increased β-catenin gene reporter activity. Hypoxia and its mimetics increased expression of the BMP antagonists gremlin and noggin and decreased Smad-1/5/8 phosphorylation. As a partial explanation for the mechanism of regulation of sclerostin by oxygen, MEF2 reporter assays revealed decreased activity. Modulation of VEGF signaling under normoxia or hypoxia revealed no influence upon Sost transcription. These data suggest that hypoxia inhibits sclerostin expression, through enhanced antagonism of BMP signaling independent of VEGF. J. Cell. Biochem. 110: 457–467, 2010.
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