Molecular and Cellular Mechanisms of Osteoporosis

描述(申请人提供)：本次续展申请的目的是提高对骨质疏松症骨脆性综合征的病理生理学的了解，从而使其治疗合理化和最优化。具体地说，它将检验相关的假设，即随着年龄的增长，骨量和强度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；脂质氧化；内源性糖皮质激素增多和自噬失败。激素疗法，如雌激素替代和间歇性促性腺激素释放激素，其疗效至少部分归功于抗氧化特性。为了实现该方案的目标，提出了三个由三个核心支持的项目。核心A将科学管理与生物统计和行政支持相结合；核心B提供转基因小鼠的设计、生产、表征和维护；核心C提供组织形态测量、DEXA、微型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ROS放大或Foxos的ROS减弱对骨骼稳态的贡献及其随年龄的变化而解除调节，ROS在雌激素对成骨细胞和破骨细胞的影响中的作用，以及这些细胞中雌激素作用的丧失对骨骼退化的贡献。具体地说，它将测试以下假设：增加ROS水平通过将β-catenin从Wnt/Tcf转移到FoxO介导的转录来抑制承诺的成骨细胞前体的生成，但增加破骨细胞的生成和存活；雌激素通过ER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Alox15介导的脂质氧化在衰老、高脂血症和雌激素丢失对骨骼稳态的不利影响中的作用，以及氧化的脂质通过FoxO和PPAR？介导的减少Wnt信号的作用而增强OS导致成骨细胞分化和存活减少的可能性。此外，它还将检验间歇性甲状旁腺激素通过减少p66shc的激活，抑制Alox15的表达，增加Aldh3a1等抗氧化酶的合成，从而增强Wnt信号和增加骨形成来降低OS的假设。最后，项目3将继续这一项目的开创性发现，即内源性糖皮质激素通过增加OS直接刺激骨细胞凋亡，从而导致与年龄相关的骨量和强度的下降，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。 与公共健康相关：这项工作应该加深我们对老龄化如何易于发生骨质疏松症，从而增加老年人骨折风险的理解。这样的理解可能被证明有助于确定调节再生反应的策略，并开发靶向药物，以同时预防(甚至逆转)骨质疏松症和其他由衰老和氧化应激引起的退行性疾病。 对独立组件的回顾 核心A：管理、行政和生物统计核心；斯塔夫罗斯·C·马诺拉加斯博士，核心领导(CL) 说明(申请人提供)：与过去一样，管理、行政和生物统计核心(A)的目标是通过将科学管理、行政支助、生物统计专门知识和共同设备维护纳入单一核心职能，协助三个项目和另外两个核心，并以集中和协调的方式提供这些服务。为了实现其目标，核心将追求以下具体目标：提供科学的领导和管理，并监测进展和遵守研究目标。这将由PI和副项目主任Jilka博士和O‘Brien博士完成。核心还将提供行政支助。这将由PI和该计划项目的管理员Mark Mosby完成。莫斯比先生也是骨质疏松症和新陈代谢骨病中心以及内分泌和新陈代谢部门的医疗服务经理。莫斯比先生将得到骨质疏松症和代谢性骨病中心以及内分泌和新陈代谢部门的其他管理人员的帮助。此外，CORE A将提供UAMS生物统计系主任罗伯逊博士和受过硕士训练的生物统计研究助理托斯滕森先生提供的生物统计学专业知识。最后，该核心将负责集中维护通用设备。 与公共健康相关：协调一个大型项目的工作，该项目研究老年人如何变得容易患骨质疏松性骨折，应该会更容易理解潜在的疾病及其原因。此外，它还应促进协调可能导致发现可同时预防(甚至逆转)骨质疏松症和抗击老年引起的其他退行性疾病的治疗方法的努力。

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.