Androgen action in bone: Overexpression of AR

骨质疏松症是一种以低骨量和骨骼微结构受损为特征的代谢性骨病 这会增加骨骼的脆弱性，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展风险的重要决定因素， 是另一个重要的决定因素。骨质疏松症往往伴随着性腺功能减退状态在这两个男人 但雄激素和雌激素对骨骼的影响仍然很难确定。 雌激素被认为通过抑制破骨细胞的骨吸收而起作用，即作为抗吸收剂。 这些药物可以保护骨骼免受进一步的骨质流失。非芳香化雄激素，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， 因此代表了重要的治疗类别。雄激素作用的一个靶点是骨膜 间室，激活导致骨大小增加，被认为是骨骼差异的基础。 在雄性和雌性之间观察到的大小，但机制仍有争议。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。我们已经开发了一种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靶向不同的成骨细胞群体; 3.6 AR-（自动减阻） 在骨膜和整个成骨细胞谱系中AR过表达的转基因小鼠与对照组相比，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种新的模型， 表征骨中雄激素反应性而无需全身施用激素。具体目标 1，我们将定义AR信号传导对小鼠骨骼发育的贡献， 与雄激素的关系。在具体目标2中，我们将描述分子和细胞 成骨细胞模型中受雄激素和雌激素影响的事件，包括骨膜和骨内膜细胞。 这些研究将确定受骨中雄激素治疗影响的特定分子事件/途径， 并应导致对影响成人骨骼大小和质量的机制的更好理解。

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.