Molecular and Cellular Mechanisms of Osteoporosis

描述（由申请人提供）：本次续期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认识，从而使其治疗合理化和优化。具体来说，它将检验相关的假设，即骨量和强度随着年龄的增长而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；脂质氧化;内源性高糖皮质激素症和自噬失败。激素疗法，如雌激素替代和间歇性RTH，其疗效至少部分归功于抗氧化特性。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和行政支持相结合；Core B提供转基因小鼠的设计、生产、表征和维护；Core C提供组织形态测量、DEXA、micro-CT和生物力学测量。项目1将确定成骨细胞和破骨细胞中p66shc的活性氧（ROS）扩增或FoxOs的ROS衰减对骨骼稳态的贡献及其随着年龄的增长而失调，ROS在雌激素对成骨细胞和破骨细胞的影响中的作用，以及这些细胞类型中雌激素作用的丧失对骨骼退化的贡献。具体来说，它将测试ROS水平升高通过转移来抑制成骨细胞前体生成的假设

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.