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：
9919470
负责人：
Martin J J Ronis
金额：
$ 45.31万
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/9919470
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 Line Cells Characteristics Colony-forming units Complex Cultured Cells 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 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 PPAR gamma Pathway interactions Production Rattus Reactive Oxygen Species Regulation Research Risk Risk Factors Role Serum Signal Transduction Signaling Molecule Skeletal Muscle Source Surface T-Lymphocyte TNF gene TP53 gene Testing Toxic effect Transgenic Mice Vitamin E Wild Type Mouse Woman adipocyte differentiation age related alcohol effect alcohol prevention alpha Tocopherol beta catenin 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 progenitor public health relevance receptor response self-renewal senescence stem cell differentiation stem cells tissue injury 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，但对于女性酒精毒性的分子机制（尤其是与骨骼相关的分子机制）知之甚少。成年早期酗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。由此导致的峰值骨量减少将使女性在以后的生活中容易患骨质疏松症。乙醇对骨骼产生毒性作用的分子机制仍知之甚少。乙醇抑制骨形成。喂养 EtOH 的雌性大鼠和小鼠的骨质流失可被膳食抗氧化剂（包括 N-乙酰半胱氨酸和维生素 E）以及 DPI（一种 NADPH 氧化酶 (NOX) 抑制剂）所阻止。然而，在缺乏活性 NOX1/2 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。我们假设活性氧 (ROS) 的另一种来源介导了乙醇对骨形成的影响。 NOX 4 -/- 小鼠的离体骨髓培养物将用于测试以下假设：NOX4 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。小鼠液体饮食模型将用于在成骨细胞前体中细胞特异性消除 NOX4 的小鼠（Prx-1-Cre-lox 小鼠）体内测试这一假设。或者，将使用线粒体 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。在酗酒的较高浓度特征下，EtOH 还可以通过诱导 RANKL 增加骨吸收，RANKL 是主要在骨细胞中表达的 TNF 家族成员，通过受体 RANK 发出信号以刺激破骨细胞生成。 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将在缺乏 NOX4 或骨细胞中 NOX1/2 失活的小鼠体内测定（NOX4 和 rac-1 Dmp） -1 Cere-lox 小鼠）通过流质饮食和乙醇暴饮模型喂食乙醇。此外，还将在体外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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway.

饮酒通过激活 Wnt/β-连环蛋白信号通路促进雄性小鼠二乙基亚硝胺诱导的肝癌发生。

DOI：
发表时间：
2014-07
期刊：
影响因子：
0
作者：
Mercer, Kelly E;Hennings, Leah;Sharma, Neha;Lai, Keith;Cleves, Mario A;Wynne, Rebecca A;Badger, Thomas M;Ronis, Martin J J
通讯作者：
Ronis, Martin J J

Children's liking and wanting of foods vary over multiple bites/sips of consumption: A case study of foods containing wild blueberry powder in the amounts targeted to deliver bioactive phytonutrients for children.

儿童对食物的喜好和需求因多次咬/啜而变化：对含有野生蓝莓粉的食品进行案例研究，其含量旨在为儿童提供生物活性植物营养素。

DOI：
发表时间：
2020-05
期刊：
影响因子：
0
作者：
Seo, Han;Adams, Sean H;Howard, Luke R;Brownmiller, Cindy;Hogan, Victoria;Chen, Jin;Pramudya, Ragita C
通讯作者：
Pramudya, Ragita C

A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling.

乙醇诱导的氧化应激通过抑制 Wnt/β-连环蛋白信号传导来控制间充质基质细胞的谱系定型。

DOI：
发表时间：
2010-05
期刊：
影响因子：
0
作者：
Chen, Jin-Ran;Lazarenko, Oxana P.;Shankar, Kartik;Blackburn, Michael L.;Badger, Thomas M.;Ronis, Martin J.
通讯作者：
Ronis, Martin J.

Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats.

抑制 NADPH 氧化酶可防止雌性大鼠慢性乙醇引起的骨质流失。

DOI：
发表时间：
2011-03
期刊：
影响因子：
0
作者：
Chen, Jin;Lazarenko, Oxana P;Shankar, Kartik;Blackburn, Michael L;Lumpkin, Charles K;Badger, Thomas M;Ronis, Martin J J
通讯作者：
Ronis, Martin J J

p47phox-Nox2-dependent ROS Signaling Inhibits Early Bone Development in Mice but Protects against Skeletal Aging.

p47phox-Nox2 依赖性 ROS 信号传导抑制小鼠早期骨骼发育，但可防止骨骼老化。

DOI：
发表时间：
2015-06-05
期刊：
影响因子：
0
作者：
Chen, Jin;Lazarenko, Oxana P;Blackburn, Michael L;Mercer, Kelly E;Badger, Thomas M;Ronis, Martin J J
通讯作者：
Ronis, Martin J J