Chronic Alcohol Abuse: Suppression of Bone Remodeling in Non-human Primates

慢性酒精滥用：非人类灵长类动物骨重塑的抑制

• 批准号: 8729551
• 负责人: URSZULA T IWANIEC
• 金额: $ 7.08万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729551
• 关键词: Adult; Adverse effects; Alcohol abuse; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Applications Grants; Biological; Biological Process; Bone Density; Bone remodeling; Chronic; Data; Deterioration; Dose; Exhibits; Fatigue; Fracture; Future; General Population; Goals; Grant; Health; Heavy Drinking; Human; Individual; Intervention; Knowledge; Lead; Macaca; Macaca mulatta; Mediating; Modeling; Molecular; Monkeys; National Institute on Alcohol Abuse and Alcoholism; Oregon; Play; Positioning Attribute; Primates; Property; Rattus; Research; Research Project Grants; Risk; Risk Factors; Rodent; Rodent Model; Role; Specimen; Strategic Planning; Testing; Trauma; Work; alcohol effect; alcohol research; base; bone; bone loss; bone mass; bone metabolism; bone quality; bone strength; chronic alcohol ingestion; male; nonhuman primate; novel; osteoporosis with pathological fracture; public health relevance; repaired; skeletal

DESCRIPTION (provided by applicant): The increase in "low trauma," as well as "all cause" fractures in chronic heavy alcohol consumers greatly exceeds values predicted by the extent of bone loss, indicating that excessive drinking has detrimental effects on bone strength independent of its well-known actions to reduce bone mineral density (BMD). The mechanism for this BMD-independent effect of chronic alcohol on fracture risk is unknown. Our working hypothesis is that by inhibiting cortical bone remodeling, alcohol abuse results in deterioration o bone quality. Bone remodeling is essential to repair fatigue-generated microdamage. A dose-dependent inhibitory effect of alcohol on cancellous (spongy) bone remodeling is well established in rodent models; however, significantly less is known concerning the effects of alcohol on remodeling in cortical (compact) bone which, in humans, comprises the great majority (~80%) of bone mass and plays a crucial role in structural support. The primary objective of this application is to determine the extent to which chronic heavy alcohol consumption decreases bone strength by suppressing intracortical bone remodeling in a nonhuman primate model. To accomplish this objective, we have capitalized upon a unique opportunity to obtain bone specimens from rhesus macaque monkeys (Macaca mulatta) being studied in an ongoing NIAAA-sponsored alcohol research project conducted at the Oregon National Primate Research Center. Unlike rodents, which exhibit minimal intracortical bone remodeling, intracortical bone remodeling in macaques closely resembles intracortical bone remodeling in humans. Our central hypothesis, based in part on our preliminary data in rats and macaques, is that accumulation of microfractures will correlate closely with the BMD-independent decrease in bone strength associated with chronic heavy alcohol consumption. We propose to test this hypothesis by accomplishing one specific aim. Specific aim: Define the correlative relationships among chronic (1 year) heavy alcohol consumption, extent of intracortical bone remodeling, accumulation of bone microfractures (microdamage), and overall bone strength in adult male rhesus macaques. Based on our preliminary data, we anticipate that long-term heavy alcohol consumption in the non-human primates will result in significantly decreased bone strength which, in turn, will be correlated with reduced bone quality and suppressed levels of intracortical bone remodeling. The primary positive impact of our anticipated findings is the demonstration of "proof of principle" for a novel, BMD-independent mechanism for the increase in fracture risk observed in heavy drinkers. This knowledge is expected to establish the basis for a future R01 grant application to help define the cellular and molecular mechanisms responsible for the detrimental effects of heavy alcohol consumption on bone.

描述（由申请人提供）：“低创伤”的增加以及慢性重饮用者中的“所有原因”骨折大大超过了骨质流失程度所预测的价值，这表明饮酒过多对骨强度有害，独立于其众所周知的行动，以减少骨矿物质密度（BMD）。慢性酒精对骨折风险的这种非依赖BMD的作用的机制尚不清楚。我们的工作假设是，通过抑制皮质骨重塑，酗酒会导致骨质质量恶化。骨重塑对于修复疲劳生成的微型塑料至关重要。酒精对取消（海绵状）骨重塑的剂量依赖性抑制作用在啮齿动物模型中已很好地确定。然而，关于酒精对皮质（紧凑）骨重塑的影响的影响要少得多，这在人类中包括绝大多数（约80％）的骨骼质量，并且在结构支持中起着至关重要的作用。该应用的主要目的是确定慢性重饮用量通过在非人类灵长类动物模型中抑制皮质内骨重塑来降低骨强度的程度。为了实现这一目标，我们已经利用了一个独特的机会，可以从俄勒冈州国家灵长类动物研究中心进行的NIAAA赞助的酒精研究项目中研究从恒河猴猕猴（Macaca Mulatta）获得骨头标本。与啮齿动物表现出最小的皮质内骨重塑不同，猕猴中的皮质内骨重塑与人类的心脏内骨重塑相似。我们的中心假设部分基于我们在大鼠和猕猴中的初步数据，是微裂缝的积累将与与慢性重饮酒有关的骨强度无关降低密切相关。我们建议通过实现一个具体目标来检验这一假设。具体目的：定义慢性（1年）大量酒精消耗的相关关系，心脏内骨重塑的程度，骨骼微裂缝的积累（微骨）和成人雄性恒河猕猴的整体骨骼强度。根据我们的初步数据，我们预计非人类灵长类动物的长期大量酒精消耗将导致骨强度显着降低，这反过来又将与骨质降低和抑制程度的心脏内骨重塑相关。我们预期的发现的主要积极影响是一种新颖的，独立于BMD的机制的“原理证明”，以增加在重饮者中观察到的骨折风险的增加。这些知识有望为未来的R01赠款应用建立基础，以帮助定义导致大量饮酒对骨骼的有害影响的细胞和分子机制。