Molecular and Cellular Mechanisms of Osteoporosis

描述（由申请人提供）：本次更新申请的目的是提高对骨质疏松症骨脆性综合征病理生理学的理解，从而合理化和优化其治疗。具体而言，它将测试相关的假设，即骨量和强度随年龄的下降是一个多因素的过程，氧化应激（OS）是几种不同机制的共同潜在罪魁祸首，包括衰老本身;性类固醇缺乏症;脂质氧化;内源性糖皮质激素过多和自噬失败。激素疗法，如雌激素替代疗法和间歇性RTH，至少部分归功于抗氧化剂的特性。为实现该计划的目标，提出了三个核心支持的三个项目。核心A将科学管理与生物统计学和行政支持相结合;核心B提供转基因小鼠的设计、生产、表征和维护;核心C提供组织形态学、DEXA、显微CT和生物力学测量。项目1将确定成骨细胞和破骨细胞中p66 shc引起的活性氧（ROS）扩增或FoxOs引起的ROS衰减对骨骼稳态的贡献及其随年龄的失调，ROS在雌激素对成骨细胞和骨细胞的作用中的作用，以及这些细胞类型中雌激素作用丧失对骨骼退化的贡献。具体地说，它将测试的假设，增加活性氧水平抑制生成的承诺成骨细胞前体，通过转移 β-连环蛋白从Wnt/Tcf到FoxO介导的转录，但增加破骨细胞的生成和存活;雌激素通过ERα介导的细胞自主抗氧化作用拮抗这两种作用。项目2将研究Alox 15介导的脂质氧化对衰老、高脂血症和雌激素丢失对骨骼稳态的不良影响的作用，以及氧化脂质通过FoxO和PPARγ介导的减少Wnt信号传导的作用增强OS导致成骨细胞分化和存活减少的可能性。此外，它将测试间歇性PTH通过降低p66 shc激活、抑制Alox 15表达和增加抗氧化酶如Aldh 3a 1的合成来降低OS，从而导致Wnt信号传导增强和骨形成增加的假设。最后，项目3将继续研究该项目的开创性发现，即内源性糖皮质激素通过增加OS直接刺激骨细胞凋亡，从而导致骨量和强度的年龄相关性下降，而这与自噬过程相反，自噬过程随着年龄的增长而变得不那么有效。

DESCRIPTION (provided by applicant): The goal of this renewal application is to improve the understanding of the pathophysiology of the bone fragility syndrome of osteoporosis and, thereby, rationalize and optimize its treatment. Specifically, it will test the interrelated hypotheses that the decline in bone mass and strength with age is a multi-factorial process and oxidative stress (OS) is a common underlying culprit of several different mechanisms, including aging per se; sex steroid deficiency; lipid oxidation; and endogenous hyperglucocorticoidism and failure of autophagy. Hormone therapies, such as estrogen replacement and intermittent RTH, owe their efficacy, at least in part, to antioxidant properties. To achieve the goal of the Program, three projects supported by three cores are proposed. Core A combines scientific management with biostatistics and administrative support; Core B provides design, production, characterization, and maintenance of genetically modified mice; and Core C provides histomorphometry, DEXA, micro-CT, and biomechanical measurements. Project 1 will determine the contribution of reactive oxygen species (ROS) amplification by p66shc or ROS attenuation by FoxOs in osteoblasts and osteoclasts to skeletal homeostasis and its deregulation with aging, the role of ROS in the effects estrogens on osteoblastic and osteoclastic cells, and the contribution of the loss of estrogen action in these cell types to skeletal involution. Specifically, it will test the hypotheses that increased ROS levels restrain te generation of committed osteoblast precursors by diverting ß-catenin from Wnt/Tcf to FoxO-mediated transcription, but increase osteoclast generation and survival; and that estrogens antagonize both of these effects by cell autonomous antioxidant actions mediated by ERα. Project 2 will investigate the contribution of Alox15-mediated lipid oxidation to the adverse effects of aging, hyperlipidemia, and loss of estrogens on skeletal homeostasis, and the possibility that oxidized lipids intensify OS leading to reduced differentiation and survival of osteoblasts via FoxO- and PPARγ-mediated actions that decrease Wnt signaling. In addition it will test the hypothesis that intermittent PTH decreases OS by decreasing p66shc activation, suppressing Alox15 expression, and increasing the synthesis of antioxidant enzymes like Aldh3a1, leading to augmented Wnt signaling and increased bone formation. Finally, Project 3 will pursue seminal discoveries of this program that endogenous glucocorticoids contribute to the age-associated decrease in bone mass and strength by directly stimulating osteocyte apoptosis via increased OS and that this is opposed by the process of autophagy, which becomes less efficient with age.