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：
Martin J J Ronis
金额：
$ 49.58万
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/9126707
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 Culture Techniques Cell Line Cells Characteristics Colony-forming units Complement Factor B Complex Consumption Data Daughter Development Diet Disease Elderly Enzymes Ethanol 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 Metabolism 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 TNFSF11 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 cytokine dietary antioxidant diphenyleneiodonium drinking emerging adult feeding in vivo inhibitor/antagonist injury and repair insight knock-down member men older women osteoclastogenesis osteogenic prevent progenitor public health relevance receptor response self-renewal senescence stem cell differentiation transcription factor 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（由申请人提供）：虽然众所周知，女性比男性更容易受到乙醇（EtOH）的毒性作用，但对于酒精中毒（尤其是女性）与骨骼相关的酒精毒性的分子机制知之甚少。成年早期饮酒会导致骨骼生长受损，在美国，大约 20% 的 18-30 岁女性（440 万人）酗酒，导致峰值骨量减少，使女性在以后容易患骨质疏松症。 EtOH 对骨骼产生毒性作用的分子机制仍知之甚少。EtOH 会抑制雌性大鼠和小鼠的骨质流失，而 N-乙酰半胱氨酸和维生素 E 等抗氧化剂饮食以及 DPI 抑制剂可阻止其骨质流失。然而，在缺乏活性的 p47phox -/- 小鼠中，EtOH 抑制成骨细胞生成和刺激骨髓肥胖的作用并未被阻断。 NOX1/2。我们发现活性氧 (ROS) 的另一种来源介导 EtOH 对骨形成的影响，我们将利用 NOX 4 -/- 小鼠的离体骨髓培养物来检验 NOX4 介导该影响的假设。乙醇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将用于在小鼠体内通过细胞特异性消融 NOX4 来测试这一假设。或者，使用线粒体 ROS 抑制剂 mitoTEMPO 来测试线粒体衍生的 ROS 在乙醇抑制骨形成中的作用。在酗酒的较高浓度下，乙醇也可以增加骨质。通过诱导 RANKL 进行吸收，RANKL 是 TNF 家族的成员，主要在骨细胞中表达，通过受体 RANK 发出信号来刺激破骨细胞生成。 EtOH 诱导的骨细胞 RANKL 产生以及 EtOH 对骨细胞功能和皮质骨形态的其他影响将在骨细胞中缺乏 NOX4 或 NOX1/2 失活的小鼠（NOX4 和 rac-1 Dmp-1 Cere-lox 小鼠）体内测定此外，还将在骨细胞中测试乙醇代谢过程中产生的过量 NADH 在 NOX 激活中的作用。体外。