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：
9344518
负责人：
Martin J J Ronis
金额：
$ 47.28万
依托单位：
LSU HEALTH SCIENCES CENTER
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

来源：
https://reporter.nih.gov/project-details/9344518
关键词：
Ablation Acetylcysteine Adipocytes Affect Age Aging Alcohol abuse Alcohol consumption Alcohols Alkaline Phosphatase Antioxidants Apoptosis Applications Grants Area Bone Development Bone Formation Inhibition Bone Growth Bone Marrow Bone Marrow Cells Bone Resorption Bone remodeling Cell Differentiation process Cell Line Cells Characteristics Colony-forming units Complex Cultured Cells Data Daughter Development Diet Disease Elderly Enzymes Ethanol Metabolism Ethanol toxicity Family Family member Female Fibroblasts Funding Heavy Drinking Human Hydrogen Peroxide Impairment In Vitro Inflammation Injury Investigation Knock-out Ligands Link Liquid substance Mediating Menopause Mesenchymal Stem Cells Messenger RNA Mitochondria Modeling Molecular Morphology Mus NADH NADPH Oxidase NIH Program Announcements National Institute on Alcohol Abuse and Alcoholism Nuclear Obesity Osteoblasts Osteocalcin Osteoclasts Osteocytes Osteogenesis Osteopenia Osteoporosis Oxidative Stress Pathway interactions Peroxisome Proliferator-Activated Receptors Production Rattus Reactive Oxygen Species Regulation Research Risk Risk Factors Role Serum Signal Transduction Signaling Molecule Skeletal Muscle Source Stem cells Surface T-Lymphocyte TNF gene TP53 gene Testing Tissues Tocopherols Toxic effect Transgenic Mice Vitamin E Wild Type Mouse Woman adipocyte differentiation age related alcohol effect binge drinking body system bone bone cell bone loss bone mass bone turnover catalase cortical bone cytokine dietary antioxidant diphenyleneiodonium drinking emerging adult in vivo inhibitor/antagonist injury and repair insight knock-down member men older women osteoblast differentiation osteoclastogenesis osteogenic prevent progenitor public health relevance receptor response self-renewal senescence transcription factor treatment effect young woman

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（由适用提供）：尽管众所周知，女性比男性更容易受到乙醇（ETOH）的毒性作用的影响，但对女性酒精毒性的分子机制的了解少得多，尤其是与骨骼相关。成年初期的酗酒会导致骨骼生长受损，在美国约有20％的18-30岁（440万）暴饮暴食。峰值骨质量的降低会使女性在后来的骨质疏松症中易于骨质疏松。 EtOH对骨骼毒性作用的基础机制仍然尚不清楚。 ETOH抑制骨形成。雌性大鼠和喂养ETOH的小鼠的骨质流失被包括N-乙酰半胱氨酸和维生素E（NADPH氧化物（NOX）酶抑制剂的饮食中抗氧化剂阻塞。然而，在缺乏活性NOX1/2的P47phox - / - 小鼠中，ETOH对抑制成骨细胞生成和刺激骨髓肥胖的作用没有阻塞。我们假设一个活性氧（ROS）的另一种来源介导了EtOH对骨形成的影响。 NOX 4 - / - 小鼠的前体骨髓培养物将用于检验以下假设，即NOX4介导了EtOH诱导的间充质干细胞自我更新和分化成整骨细胞或脂肪细胞的影响。小鼠液体饮食模型将用于在成骨细胞前体（PRX-1-CRE-LOX小鼠）中具有细胞特异性nox4的细胞特异性消融的小鼠中的体内测试。线粒体衍生的ROS在骨形成中的ETOH抑制在骨骼形成中的作用将用于使用线粒体的骨骼形成抑制作用。在暴饮暴食的浓度较高的特征下，ETOH还可以通过诱导RANKL来增加骨骼分辨率，RANKL是TNF家族的一个成员，主要在骨细胞中表达，该家族通过受体等级发出信号以刺激骨质现代发生。在缺乏NOX4的小鼠中，将确定Nox衍生的ROS在ETOH诱导的RASL产生中的RASL产生以及EtOH对骨细胞功能和皮质骨形态的其他作用，而在体内将确定缺乏NOX1/2的NOX1/2在骨细胞中的NOX1/2中（NOX4和RAC-1 DMP-1 dmp-1 dmp-1 cere-ceere-aNtoh Mote and difice note eTH）。另外，在ETOH代谢中产生的过量NADH在NOX激活中的作用将在体外在骨细胞中进行测试。