Androgen action in bone: Overexpression of AR

描述(申请人提供)：骨质疏松症是一种骨量低、骨骼微结构受损的代谢性骨病，会增加骨骼的脆性，从而增加骨折的风险。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。在男性和女性中，骨质疏松症通常伴随性腺功能低下状态，但雄激素和雌激素对骨骼的影响仍然缺乏特征性。雌激素被认为是通过抑制破骨细胞的骨吸收而起作用的，即作为抗吸收剂，保护骨骼免受进一步的骨丢失。非芳香化雄激素，如5α-二氢睾酮(DHT)，是通过刺激骨形成增加骨量的合成代谢剂，因此代表着一个重要的治疗类别。雄激素作用的一个靶点是骨膜室，激活导致骨大小增加，这被认为是男性和女性骨骼大小差异的基础，但其机制仍有争议。我们假设雄激素通过成骨细胞系中的雄激素受体(AR)介导的作用来影响骨形成和骨大小。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的工具。AR转基因系通过使用两种不同的启动子，显示针对不同成骨细胞群体的AR过表达；col3.6 AR转基因小鼠的AR过度表达在骨膜和整个成骨细胞系中；而col2.3 AR转基因小鼠的过度表达仅限于矿化成熟成骨细胞。我们认为，对照和选择性靶向AR转基因株系之间的差异将提供一种新的模型来表征骨中雄激素的反应，而不需要全身注射激素。在特定的目标1中，我们将确定AR信号在不同成骨细胞群中对雄激素敏感性增强的小鼠骨骼发育中的作用。在特定的目标2中，我们将在成骨细胞模型中表征雄激素和雌激素影响的分子和细胞事件，包括骨膜和骨内膜细胞。这些研究将确定骨骼中雄激素治疗影响的特定分子事件/途径，并应有助于更好地理解影响成人骨骼大小和质量的机制。

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.