The role of osteocytes in alcohol-induced osteopenia

骨细胞在酒精引起的骨质减少中的作用

• 批准号: 10492813
• 负责人: Alexandra Denys
• 金额: $ 0.25万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-13 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10492813
• 关键词: Achievement; Acute; Address; Adolescence; Adolescent; Adult; Affect; Alcohol consumption; Alcohols; Anabolism; Biological Markers; Bone Density; Bone Diseases; Bone Formation Inhibition; Bone Matrix; Bone Resorption; Carrying Capacities; Cells; Chronic; Clinical; Clinical Management; Collagen; Complex; Data; Deposition; Development; Diagnosis; Disease Management; Dose; Elasticity; Ensure; Ethanol; Exposure to; Fracture; Goals; HIV; Homeostasis; Human; Impairment; In Vitro; Life; Link; Literature; Macaca mulatta; Measurement; Mediating; Mediator of activation protein; Molecular; Morphology; Mus; Musculoskeletal; Musculoskeletal Diseases; Osteoclasts; Osteocytes; Osteogenesis; Osteogenesis Imperfecta; Osteolysis; Osteopenia; Osteoporosis; Pathway interactions; Patients; Physiologic calcification; Physiological; Play; Process; Production; Proteins; Reporting; Research; Risk; Risk Factors; Role; SIV; Sampling; Serum; Signal Transduction; Spinal; System; Testing; Transforming Growth Factor beta; Translating; WNT Signaling Pathway; alcohol effect; antiretroviral therapy; bone; bone cell; bone fragility; bone health; bone mass; bone quality; bone strength; chronic alcohol ingestion; cohort; comorbidity; design; emerging adult; epidemiology study; fracture risk; in vivo; inhibitor; insight; interest; mechanical properties; mineralization; nonhuman primate; novel; osteoblast differentiation; osteoporosis with pathological fracture; problem drinker; translational study

PROJECT SUMMARY/ABSTRACT Numerous epidemiological studies support that heavy alcohol consumption is linked to lower bone mineral density (BMD), a significant risk factor for the development of osteoporosis. Early life alcohol use is particularly undermining to bone health in adulthood as the result of impaired attainment of peak bone mass, a concerning finding considering the increasing rate of alcohol consumption in adolescents. Confounding the problem, ethanol also compromises bone’s mechanical properties, which decreases bone quality and increases fracture risk, even in the absence of decreased bone mass. Clinically, measurements of bone quality aren’t implemented, nor is this aspect routinely considered in bone disease management. The literature strongly suggests that osteocytes play a pivotal role in maintaining bone quality, yet the effects of alcohol on these cells and their processes are poorly understood. Osteocytes have been recently appreciated to actively deposit and resorb bone in their microenvironment, a process called perilacunar/canalicular remodeling (PLR). PLR mediators ensure proper collagen organization and bone mineralization. Further, osteocytes are pivotal in bone homeostasis through their release of cell specific proteins, such as sclerostin. This protein is of particular interest as it inhibits a pro- osteoblastic pathway (Wnt signaling) that is known to be inhibited by ethanol. Importantly, sclerostin also modulates PLR, specifically promoting acidification to allow for perilacunar resorption (osteocytic osteolysis). Finally, both PLR and sclerostin production are regulated by TGF-ß signaling, an important bone anabolic pathway known to be dysregulated in musculoskeletal diseases marked by decreased quality. The studies proposed in this application are designed to uncover how, mechanistically, alcohol affects osteocytes, and the extent to which these effects prevail in a complex physiological system. The overall hypothesis is that ethanol increases TGF-ß signaling in osteocytes, which promotes sclerostin release and disrupts PLR, resulting in fragile bone. Specific Aim 1 will use in vitro and in vivo studies to assess how ethanol alters PLR and the osteocyte microenvironment, and whether these changes significantly increase fracture risk. Specific Aim 2 will analyze serum samples from a human clinical cohort and a rhesus macaque study to see whether ethanol consumption results in increased serum sclerostin, which could act as a useful biomarker for PLR status. Specific Aim 3 investigates a mechanistic pathway uniting these two phenomena and uses again in vitro and in vivo studies to determine if TGF-ß signaling is at the core of the observed changes. Altogether, these studies will generate new mechanistic insights into the role of osteocytes in alcohol-induced osteopenia and allow to narrow the clinical gap that exists in treating quality-driven musculoskeletal conditions.

项目总结/摘要 大量的流行病学研究表明，大量饮酒与骨矿物质含量降低有关 骨密度（BMD）是骨质疏松症发生的重要危险因素。早期饮酒尤其是 由于达到峰值骨量受损，成年后骨骼健康受到破坏，这是一个令人担忧的问题， 这一发现考虑到青少年饮酒率的上升。混淆问题的是乙醇 也会损害骨骼的机械性能，从而降低骨骼质量并增加骨折风险， 在没有骨量减少的情况下。临床上，骨质测量没有实施， 这方面在骨病管理中被常规考虑。文献强烈提示骨细胞 在维持骨质量方面起着关键作用，但酒精对这些细胞及其过程的影响是 不太了解。骨细胞最近被认为在其骨基质中积极地存款和再吸收骨。 微环境，一个过程称为泡周/泪小管重塑（PLR）。PLR调解员确保适当的 胶原组织和骨矿化。此外，骨细胞通过其自身的功能在骨稳态中是关键的。 释放细胞特异性蛋白质，如硬化蛋白。这种蛋白质是特别感兴趣的，因为它抑制了一种前- 成骨细胞途径（Wnt信号传导），已知其被乙醇抑制。重要的是，硬化蛋白还 调节PLR，特别是促进酸化，以允许周围骨吸收（骨细胞性骨质溶解）。 最后，PLR和硬化蛋白的产生都受到TGF-β信号的调节，TGF-β信号是一种重要的骨合成代谢途径。 已知在肌肉骨骼疾病中失调的信号通路，其特征在于质量下降。研究 本申请中提出的方法旨在揭示酒精如何机械地影响骨细胞， 这些影响在复杂的生理系统中占主导地位的程度。总的假设是乙醇 增加骨细胞中的TGF-β信号传导，促进硬化蛋白释放并破坏PLR，导致脆性 骨头具体目标1将使用体外和体内研究来评估乙醇如何改变PLR和骨细胞 微环境，以及这些变化是否会显著增加骨折风险。第2章分析 来自人类临床队列的血清样本和恒河猴研究， 导致血清硬化蛋白增加，其可以作为PLR状态的有用生物标志物。具体目标3 研究了将这两种现象结合起来的机制途径，并再次使用体外和体内研究， 确定TGF-β信号传导是否是观察到的变化的核心。这些研究将产生新的 对骨细胞在酒精诱导的骨质减少中的作用的机制性见解，并允许缩小临床 在治疗质量驱动的肌肉骨骼疾病方面存在差距。