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Androgen action in bone: Overexpression of AR

雄激素在骨中的作用：AR 的过度表达

基本信息

批准号：
7777392
负责人：
KRISTINE M. WIREN
金额：
$ 26.01万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777392
关键词：
Adult Affect Aging Anabolic Agents Androgen Receptor Androgens Animal Model Animals Apoptosis Architecture Biochemical Biological Biological Assay Biomechanics Bone Density Bone Development Bone Formation Stimulation Bone Growth Bone Resorption Inhibition Bone Surface Calcified Calvaria Cartilage Cell Culture System Cell Differentiation process Cells Child Clinical Trials Coculture Techniques Collagen Collagen Type I Communication Coupled Development Doctor of Philosophy Endosteal Cell Epiphysial cartilage Estradiol Estrogens Event Exhibits Female Fracture Gene Expression Genes Genetic Goals Gonadal Steroid Hormones Growth Hormones Hypogonadism In Situ Hybridization In Vitro Investigation Lead Life Maintenance Measurement Mediating Metabolic Bone Diseases Minerals Modeling Molecular Mus Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis Pathway interactions Periosteal Cell Periosteum Phase Phenotype Physiological Play Population Proliferating Property Puberty Receptor Signaling Regulation Research Personnel Risk Risk Factors Role Serum Signal Transduction Skeletal Development Skeleton Staining method Stains Testing Therapeutic Transactivation Transgenes Transgenic Animals Transgenic Mice Transgenic Organisms Urine Wild Type Mouse Woman age related anabolic steroid abuse bone bone loss bone mass bone quality cell type defined contribution disorder risk high school improved in vivo insight interdisciplinary approach male men mineralization mouse model novel novel therapeutics osteoblast differentiation osteoclastogenesis overexpression programs promoter receptor expression response skeletal tool transgene expression treatment strategy

项目摘要

Osteoporosis is a metabolic bone disease with low bone mass and compromised skeletal microarchitecture that increases bone fragility and, consequently, fracture risk. Total bone mass acquired during the active growth phases early in life is an important determinant of the risk of disease development, with bone quality being another important determinant. Osteoporosis is often coupled with a hypogonadal state in both men and women but the influence of androgen and estrogen on the skeleton remains poorly characterized. Estrogens are thought to act through an inhibition of bone resorption by the osteoclast, i.e. as anti-resorptive agents, which protect the skeleton from further loss of bone. Non-aromatizable androgens such as Salpha- dihydrotestosterohe (DHT), are anabolic agents that increase bone mass by stimulation of bone formation, and thus represent an important therapeutic class. One target of androgen action is the periosteal compartment, with activation leading to an increase in bone size believed to underlie differences in skeletal size observed between males and females, but the mechanisms remain controversial. We hypothesize that androgens influence bone formation and bone size through actions mediated by the androgen receptor (AR) in the osteoblastic lineage. We have developed an AR-transgenic animal model as a tool to better identify the important biological consequences of androgen action. AR-transgenic lines exhibit overexpressionof the AR targeted to distinct osteoblastic populations through the use of two different promoters; co!3.6 AR- transgenic mice with AR overexpression in the periosteum and throughout the osteoblast lineage vs. co!2.3 AR-transgenic mice with overexpression restricted to mineralizing mature osteoblasts. We proposethat differences between controls and selectively targeted AR-transgenic lines will provide a novel model to characterize androgen responsiveness in bone without systemic administration of hormone. In Specific Aim 1, we will define the contribution of AR signaling to the developing skeleton in mice with enhanced sensitivity to androgen in distinct osteoblast populations. In Specific Aim 2, we will characterize molecular and cellular events influenced by androgen and estrogen in osteoblast models, including periosteal and endosteal cells. These studies will identify specific molecular events/pathways influenced by androgen treatment in bone, and should lead to an improved understanding of mechanisms that influence adult bone size and quality.

骨质疏松症是一种骨量低且骨骼微结构受损的代谢性骨病这会增加骨骼的脆性，从而增加骨折的风险。活动期间获得的总骨量生命早期的生长阶段是疾病发生风险的重要决定因素，骨质量是另一个重要的决定因素。骨质疏松症通常与男性的性腺功能减退症相关和女性，但雄激素和雌激素对骨骼的影响仍然知之甚少。雌激素被认为通过抑制破骨细胞的骨吸收来发挥作用，即作为抗骨吸收剂保护骨骼免受进一步骨质流失的药物。不可芳香化的雄激素，例如 Salpha- 二氢睾酮 (DHT) 是通过刺激骨形成来增加骨量的合成代谢剂，因此代表了一个重要的治疗类别。雄激素作用的目标之一是骨膜隔室，激活导致骨骼尺寸增加，据信这是骨骼差异的基础男性和女性之间观察到的大小，但其机制仍存在争议。我们假设雄激素通过雄激素受体 (AR) 介导的作用影响骨形成和骨大小在成骨细胞谱系中。我们开发了 AR 转基因动物模型作为更好地识别雄激素作用的重要生物学后果。 AR转基因株系表现出过度表达 AR 通过使用两种不同的启动子来针对不同的成骨细胞群体； co!3.6 AR- AR 在骨膜和整个成骨细胞谱系中过度表达的转基因小鼠与 co!2.3 过度表达的 AR 转基因小鼠仅限于矿化成熟成骨细胞。我们建议对照和选择性靶向 AR 转基因系之间的差异将提供一个新的模型无需全身施用激素即可表征骨中雄激素反应性。特定目标 1，我们将定义 AR 信号对敏感性增强的小鼠骨骼发育的贡献不同成骨细胞群体中的雄激素。在具体目标 2 中，我们将描述分子和细胞的特征成骨细胞模型（包括骨膜和骨内膜细胞）中受雄激素和雌激素影响的事件。这些研究将确定受雄激素治疗影响的特定分子事件/途径，并应有助于更好地了解影响成人骨骼大小和质量的机制。