The role of oxidative stress in alcohol-induced osteopenia

氧化应激在酒精引起的骨质减少中的作用

基本信息

  • 批准号:
    9126707
  • 负责人:
  • 金额:
    $ 49.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-05-15 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Although it is well known that women are more susceptible to the toxic effects of ethanol (EtOH) than men, much less is known about the molecular mechanisms underlying alcohol toxicity in women especially as relates to bone. Alcohol abuse during early adulthood results in impaired bone growth and in the U.S.A. approximately 20% of women age 18-30 (4.4 million) binge drink. A resulting reduction in peak bone mass would predispose women to osteoporosis in later life. The molecular mechanisms underlying the toxic effects of EtOH on bone remain poorly understood. EtOH inhibits bone formation. Bone loss in female rats and mice fed EtOH is blocked by dietary antioxidants including N-acetylcysteine and vitamin E and by DPI an inhibitor of NADPH oxidase (NOX) enzymes. However, effects of EtOH to inhibit osteoblastogenesis and stimulate bone marrow adiposity were not blocked in p47phox -/- mice lacking active NOX1/2. We hypothesize that another source of reactive oxygen species (ROS) mediates the effects of EtOH on bone formation. Ex-vivo bone marrow cultures from NOX 4 -/- mice will be utilized to test the hypothesis that NOX4 mediates the effects EtOH-induced inhibition of mesenchymal stem cell self-renewal and differentiation into osteoblasts or adipocytes. A mouse liquid diet model will be used to test this hypothesis in vivo in mice with cell specific ablation of NOX4 in osteoblast precursors (Prx-1-Cre-lox mice). Alternatively, the role of mitochondrial derived ROS in EtOH inhibition of bone formation will be tested using the mitochondrial ROS inhibitor mitoTEMPO. At higher concentrations characteristic of binge drinking, EtOH can also increase bone resorption via induction of RANKL, a member of the TNF family expressed primarily in osteocytes, which signals through the receptor RANK to stimulate osteoclastogenesis. The role of NOX derived ROS in EtOH-induced RANKL production from osteocytes and other effects of EtOH on osteocyte function and cortical bone morphology will be determined in vivo in mice lacking NOX4 or with inactive NOX1/2 in osteocytes (NOX4 and rac-1 Dmp-1 Cere-lox mice) fed EtOH via liquid diet and in an EtOH binge drinking model. In addition, the role of excess NADH produced during EtOH metabolism in NOX activation will be tested in bone cells in vitro.
 描述(由申请人提供):尽管众所周知女性比男性更容易受到乙醇(EtOH)毒性作用的影响,但对女性酒精毒性的分子机制知之甚少,尤其是与骨相关的机制。成年早期的酒精滥用会导致骨骼生长受损,在美国,大约20%的18-30岁的女性(440万人)酗酒。由此导致的峰值骨量减少将使妇女在以后的生活中容易患骨质疏松症。EtOH对骨毒性作用的分子机制仍然知之甚少。EtOH抑制骨形成。喂食乙醇的雌性大鼠和小鼠的骨丢失被膳食抗氧化剂(包括N-乙酰半胱氨酸和维生素E)和DPI(NADPH氧化酶(NOX)的抑制剂)阻断。然而,EtOH抑制成骨细胞生成和刺激骨髓肥胖的作用在缺乏活性NOX 1/2的p47 phox-/-小鼠中没有被阻断。我们推测,另一个来源的活性氧(ROS)介导的影响,乙醇对骨形成。来自NOX 4 -/-小鼠的离体骨髓培养物将用于检验NOX 4介导EtOH诱导的间充质干细胞自我更新和分化成成骨细胞或脂肪细胞的抑制作用的假设。小鼠流质饮食模型将用于在小鼠体内测试该假设,其中成骨细胞前体中的NOX 4具有细胞特异性消融(Prx-1-Cre-lox小鼠)。或者,将使用线粒体ROS抑制剂mitoTEMPO测试线粒体衍生的ROS在EtOH抑制骨形成中的作用。在具有酗酒特征的较高浓度下,EtOH还可通过诱导RANKL(主要在骨细胞中表达的TNF家族成员)增加骨吸收,RANKL通过受体RANK发出信号刺激破骨细胞生成。将在通过流质饮食喂食EtOH的骨细胞中缺乏NOX 4或NOX 1/2失活的小鼠(NOX 4和rac-1 Dmp-1 Cere-lox小鼠)和EtOH狂饮模型中,体内测定NOX衍生的ROS在EtOH诱导的骨细胞RANKL产生中的作用以及EtOH对骨细胞功能和皮质骨形态的其他影响。此外,将在体外骨细胞中测试EtOH代谢期间产生的过量NADH在NOX活化中的作用。

项目成果

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Martin J J Ronis其他文献

Martin J J Ronis的其他文献

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{{ truncateString('Martin J J Ronis', 18)}}的其他基金

The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
  • 批准号:
    10406154
  • 财政年份:
    2021
  • 资助金额:
    $ 49.58万
  • 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
  • 批准号:
    10608146
  • 财政年份:
    2021
  • 资助金额:
    $ 49.58万
  • 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
  • 批准号:
    9344518
  • 财政年份:
    2016
  • 资助金额:
    $ 49.58万
  • 项目类别:
The role of oxidative stress in alcohol-induced osteopenia
氧化应激在酒精引起的骨质减少中的作用
  • 批准号:
    9919470
  • 财政年份:
    2016
  • 资助金额:
    $ 49.58万
  • 项目类别:
Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy
金雀异黄素/大豆预防乙醇诱导的肝癌发生
  • 批准号:
    8354189
  • 财政年份:
    2012
  • 资助金额:
    $ 49.58万
  • 项目类别:
Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy
金雀异黄素/大豆预防乙醇诱导的肝癌发生
  • 批准号:
    8547039
  • 财政年份:
    2012
  • 资助金额:
    $ 49.58万
  • 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
  • 批准号:
    8497553
  • 财政年份:
    2009
  • 资助金额:
    $ 49.58万
  • 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
  • 批准号:
    8299084
  • 财政年份:
    2009
  • 资助金额:
    $ 49.58万
  • 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
  • 批准号:
    7890356
  • 财政年份:
    2009
  • 资助金额:
    $ 49.58万
  • 项目类别:
Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
酒精引起的骨吸收:氧化应激的作用
  • 批准号:
    8100109
  • 财政年份:
    2009
  • 资助金额:
    $ 49.58万
  • 项目类别:

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