Androgen action in bone: Overexpression of AR

描述（由申请人提供）：骨质疏松症是一种代谢性骨病，具有低骨量和受损的骨骼微结构，增加了骨脆性，从而增加了骨折风险。在生命早期的活跃生长阶段获得的总骨量是疾病发展风险的重要决定因素，骨质量是另一个重要决定因素。骨质疏松症通常伴随着男性和女性的性腺功能减退状态，但雄激素和雌激素对骨骼的影响仍然很难描述。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，其保护骨骼免受骨的进一步损失。非芳香化雄激素如5 α-二氢睾酮（DHT）是通过刺激骨形成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室，其活化导致骨大小增加，被认为是男性和女性之间观察到的骨骼大小差异的基础，但机制仍有争议。我们假设雄激素通过成骨细胞系中雄激素受体（AR）介导的作用影响骨形成和骨大小。我们已经开发了一种AR转基因动物模型作为一种工具，以更好地确定雄激素作用的重要生物学后果。通过使用两种不同的启动子，AR转基因系表现出靶向不同成骨细胞群体的AR过表达;在骨膜和整个成骨细胞谱系中AR过表达的col3.6 AR转基因小鼠与过表达限于矿化成熟成骨细胞的col2.3 AR转基因小鼠。我们建议，控制和选择性靶向AR转基因株系之间的差异将提供一种新的模型来表征雄激素在骨中的反应性，而无需全身给予激素。在特定目标1中，我们将确定AR信号对不同成骨细胞群体中对雄激素敏感性增强的小鼠骨骼发育的贡献。在特定目标2中，我们将描述成骨细胞模型（包括骨膜和骨内膜细胞）中雄激素和雌激素影响的分子和细胞事件。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大小和质量的机制的更好理解。

DESCRIPTION (provided by applicant): 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 5alpha- dihydrotestosterone (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 overexpression of the AR targeted to distinct osteoblastic populations through the use of two different promoters; col3.6 AR- transgenic mice with AR overexpression in the periosteum and throughout the osteoblast lineage vs. col2.3 AR-transgenic mice with overexpression restricted to mineralizing mature osteoblasts. We propose that 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.