Androgen action in bone: Overexpression of AR

骨质疏松症是一种骨量低、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。在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，与骨骼质量有关 是另一个重要的决定因素。骨质疏松症通常伴随着性腺功能减退。 和女性，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起作用的，即作为抗吸收作用。 保护骨骼免受进一步骨质流失的助剂。非芳香化雄激素，如Salpha- 二氢素(DHT)是一种合成代谢物质，通过刺激骨形成来增加骨量， 并因此代表了一个重要的治疗阶层。雄激素作用的一个靶点是骨膜 骨室，激活导致骨骼大小增加，据信这是骨骼差异的基础 在雄性和雌性之间观察到的大小，但其机制仍然存在争议。我们假设 雄激素通过雄激素受体(AR)调节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AR转基因动物模型，作为一种工具来更好地识别 雄激素作用的重要生物学后果。AR转基因品系表现出过度表达 通过使用两种不同的启动子针对不同的成骨细胞群体；co3.6 AR- AR在骨膜和整个成骨细胞系中过表达的转基因小鼠与CO AR转基因小鼠的过度表达仅限于矿化成熟的成骨细胞。我们建议 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 在不全身注射激素的情况下，表征骨骼中雄激素的反应性。以特定的目标 1，我们将确定AR信号在增强敏感性的小鼠骨骼发育中的作用 在不同的成骨细胞群体中对雄激素的作用。在特定目标2中，我们将描述分子和细胞 雄激素和雌激素对成骨细胞模型中事件的影响，包括骨膜和骨内膜细胞。 这些研究将确定雄激素治疗在骨骼中影响的特定分子事件/途径， 并将有助于更好地理解影响成人骨骼大小和质量的机制。

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.