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？-catenin从Wnt/Tcf到foxo介导的转录，但增加破骨细胞的生成和存活；雌激素通过雌激素介导的细胞自主抗氧化作用来对抗这两种作用。项目2将研究alox15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利影响的贡献，以及氧化脂质通过FoxO-和PPAR -增强OS导致成骨细胞分化和存活减少的可能性。-介导的减少Wnt信号传导的作用。此外，该研究将验证间歇性PTH通过降低p66shc激活、抑制Alox15表达、增加Aldh3a1等抗氧化酶的合成，从而导致Wnt信号增强和骨形成增加，从而降低OS的假设。最后，项目3将继续研究该项目的重大发现，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与年龄相关的下降，而这与自噬过程相反，随着年龄的增长，自噬过程的效率会降低。

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 ?-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 ER¿. 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 PPAR?-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. PUBLIC HEALTH RELEVANCE: This work should deepen our understanding of how aging predisposes to the development of osteoporosis and thereby increases the risk of fractures in the elderly. Such an understanding may prove useful for defining strategies to modulate regenerative responses and developing drugs targeting pathways that could simultaneously prevent (or even reverse) osteoporosis and other degenerative disorders caused by old age and oxidative stress. REVIEW OF INDIVUDUAL COMPONENTS CORE A: MANAGEMENT, ADMINISTRATION AND BIOSTATISTICS CORE; Dr. Stavros C. Manolagas, Core Leader (CL) DESCRIPTION (provided by applicant): As in the past, the goal of the Management, Administration and Biostatistics Core (A) is to assist the three Projects and the other two Cores by combining scientific management, administrative support, biostatistical expertise and common equipment maintenance into a single core function; and providing these services in a centralized and coordinated fashion. To achieve its goal, the Core will pursue the following specific aims: provide scientific leadership and management and monitor progress and compliance with the research objectives. This will be done by the PI and the Associate Program Directors, Drs. Jilka and O'Brien. The Core will also provide administrative support. This will be done by the PI and the Administrator of this Program Project, Mark Mosby. Mr. Mosby is also a Medical Service Manager for the Center for Osteoporosis and Metabolic Bones Diseases and the Division of Endocrinology and Metabolism. Mr. Mosby will be aided by the rest of the administrative staff of the Center for Osteoporosis and Metabolic Bone Diseases and the Division of Endocrinology and Metabolism. Furthermore, Core A will provide biostatistical expertise by Dr. Roberson, the Chair of the UAMS Department of Biostatistics, and Mr. Thostenson, a master's trained biostatistics research associate. Finally, this Core will be responsible for centralized common equipment maintenance. PUBLIC HEALTH RELEVANCE: Coordinating the work of a large program that examines how the elderly become susceptible to osteoporotic fractures should make it easier to understand the underlying disease and its causes. Moreover, it should facilitate the coordination of efforts that may lead to the discovery of treatments that could simultaneously prevent (or even reverse) osteoporosis and combat additional degenerative disorders caused by old age.