The role of osteocytes in alcohol-induced osteopenia

项目摘要/摘要 许多流行病学研究支持大量饮酒与骨矿物质减少有关。 密度(BMD)是导致骨质疏松症的重要风险因素。早年饮酒尤其是 由于达到峰值骨量的障碍，成年后对骨健康的破坏，令人担忧 考虑到青少年饮酒率的上升，这一发现。使问题变得复杂的是，乙醇 还会损害骨骼的机械性能，这会降低骨骼质量，增加骨折风险，甚至 在没有骨量减少的情况下。临床上，骨质量的测量没有实施，也没有 这方面在骨病治疗中是常规考虑的。文献强烈表明，骨细胞 在维持骨骼质量方面起着关键作用，然而酒精对这些细胞及其过程的影响是 人们对此知之甚少。最近人们认识到，骨细胞在其体内活跃地沉积和吸收骨 微环境，称为楔周/小管重塑(PLR)的过程。PLR调解员确保适当 胶原蛋白组织和骨矿化。此外，骨细胞在骨骼的动态平衡中起着关键作用。 释放细胞特有的蛋白质，如硬化素。这种蛋白质特别令人感兴趣，因为它抑制了一种前- 成骨细胞途径(Wnt信号)，已知可被乙醇抑制。重要的是，硬化素也 调节PLR，特别是促进酸化，以允许尺周骨吸收(骨细胞骨溶解)。 最后，PLR和硬化素的产生都受转化生长因子-一种重要的骨合成代谢物质的调节。 肌肉骨骼疾病中已知的不正常的通路，以质量下降为特征。这些研究 旨在揭示酒精是如何从机制上影响骨细胞的，以及 这些影响在复杂的生理系统中占优势的程度。总体假设是乙醇 增加骨细胞中的转化生长因子-B信号，从而促进硬化素的释放并破坏PLR，导致脆性 骨头。特殊目标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，以及这些变化是否显著增加骨折风险。《特定目标2》将分析 来自人类临床队列和恒河猴研究的血清样本，以了解酒精消费 结果血清硬化素升高，可作为PLR状态的有用生物标志物。具体目标3 研究了一种将这两种现象结合起来的机制途径，并再次用于体外和体内研究 确定转化生长因子-B信号是否处于观察到的变化的核心。总之，这些研究将产生新的 对骨细胞在酒精诱导的骨量减少中的作用的机械洞察，并允许缩小临床研究范围 在治疗质量驱动的肌肉骨骼疾病方面存在的差距。

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.