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：
7579837
负责人：
KRISTINE M. WIREN
金额：
$ 26.27万
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 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7579837
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.

骨质疏松症是一种代谢骨病，骨骼质量低，骨骼微体系结构受损这会增加骨骼脆弱性，从而增加骨折风险。在活动期间获得的总骨质量生命早期的生长阶段是疾病发展风险的重要决定因素，骨质质量是另一个重要的决定因素。两名男性的骨质疏松症通常与性交状态相结合和女性，但雄激素和雌激素对骨骼的影响仍然很差。雌激素被认为是通过破骨细胞抑制骨吸收的作用保护骨骼免受骨骼进一步损失的代理。不可芳香雄激素，例如salpha- Dihytotostosterohe（DHT）是合成代谢剂，通过刺激骨形成，增加骨骼质量，因此代表了重要的治疗类别。雄激素作用的一个目标是骨膜隔室，激活导致骨骼尺寸的增加，认为骨骼差异是基础的男性和女性之间观察到的大小，但机制仍然存在争议。我们假设这一点雄激素通过雄激素受体（AR）介导的作用影响骨形成和骨骼大小在成骨细胞谱系中。我们已经开发了一种AR-转基因动物模型，以更好地识别雄激素作用的重要生物学后果。 AR-转基因线表现出过表达通过使用两个不同的启动子来靶向不同的成骨细胞种群。 co！3.6 ar- 骨膜中的AR过表达的转基因小鼠在整个成骨细胞谱系中与CO！2.3 过表达的AR-转基因小鼠仅限于矿化成熟成骨细胞。我们建议控件和选择性靶向的AR-转基因线之间的差异将为您提供新的模型表征骨骼中雄激素反应性，而无需全身施用激素。在特定目标中 1，我们将定义AR信号对具有增强灵敏度的小鼠发育骨骼的贡献在不同的成骨细胞种群中雄激素。在特定的目标2中，我们将表征分子和细胞在成骨细胞模型中受雄激素和雌激素影响的事件，包括骨膜和内膜细胞。这些研究将确定受骨治疗影响的特定分子事件/途径，并应提高人们对影响成人骨骼大小和质量的机制的理解。