OSTEOBLAST SPECIFIC ABLATION OF THE PTH/PTHRP RECEPTOR

PTH/PTHRP 受体的成骨细胞特异性消融

• 批准号: 6201544
• 负责人: HENRY M. KRONENBERG
• 金额: $ 18.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201544
• 关键词: bone density; bone development; bone metabolism; genetically modified animals; histology; hormone receptor; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; osteoblasts; osteoclasts; parathyroid hormone related protein; parathyroid hormones

Parathyroid hormone (PTH) is the best characterized of the small group of agents that increase bone formation and may become part of a therapy for osteoporosis capable of restoring normal bone mass in this patient group. The actions of parathyroid hormone are mediated by a common receptor for both PTH and PTH-related protein (PTHrP) and involve increases in both bone formation and resorption. The goal of this proposal is to evaluate, in vivo, the roles of PTH and PTH~P in regulating osteoblast and osteoclast development and function by specifically deleting the PTH/PTHrP receptor gene from cells of the osteoblast lineage. The first aim will be to establish lines of mice selectively missing the PTH/PTHrP receptor gene only in osteoblasts of varying degrees of maturity. The cre-lox system will be used to generate mice missing the PTH/PTHrP receptor gene in osteoblasts that express the alpha1(I) collagen gene promoter and in those that express the osteocalcin gene promoter. The second aim will be to assess the role of the PTH/PTHrP receptor in osteoblast development and function. Histomorphometry, BRdU labeling, and in situ hybridization will be used to assess abnormalities of osteoblast development and function. Comparisons of the two types of cre-lox mice will clarify the relative roles of osteoblasts of varying degrees of maturity. Mice missing the PTH gene will be used to assess the individual roles of PTH and PTHrP in activating the PTH/PTHrP receptor to control osteoblast development and function. The third aim will be to assess the role of the PTH/PTHrP receptor in osteoclast development and function. Histomorphometry, urinary markers of bone resorption, and in situ hybridization will be used to assess abnormalities of osteoclast development and function. Comparisons of the two types of cre-lox mice and the use of mice missing the PTH gene will clarify the roles of osteoblasts of differing levels of maturity and the relative roles of PTH and PTHrP. These studies will lead to a better understanding of the potentially conflicting actions of PTH on bone and may lead to more effective use of PTH-like drugs in the treatment of osteoporosis.

甲状旁腺激素(PTH)是小群体中最具特点的 促进骨形成并可能成为治疗的一部分的药物 治疗骨质疏松症患者能恢复正常骨量 一群人。甲状旁腺激素的作用由一种常见的 甲状旁腺激素受体及甲状旁腺激素相关蛋白 骨形成和骨吸收的增加。这样做的目的是 建议在体内评价甲状旁腺素和甲状旁腺素在 通过调节成骨细胞和破骨细胞的发育和功能 特异性删除PTH/PTHrP受体基因 成骨细胞谱系。第一个目标是建立小鼠品系 仅在成骨细胞中选择性缺失PTH/PTHrP受体基因 不同程度的成熟。Cre-lox系统将用于 在成骨细胞中产生缺失PTH/PTHrP受体基因的小鼠 表达α1(I)胶原基因启动子 骨钙素基因启动子。第二个目标是评估 甲状旁腺素/甲状旁腺素受体在成骨细胞发育和功能中的作用。 将使用组织形态计量学、BRdU标记和原位杂交 评估成骨细胞发育和功能的异常。 对这两种类型的cre-lox小鼠的比较将澄清 不同成熟度的成骨细胞的作用。老鼠错过了 甲状旁腺素基因将被用来评估甲状旁腺激素和甲状旁腺激素受体的个体作用 激活PTH/PTHrP受体调控成骨细胞发育 功能。第三个目标是评估甲状旁腺素/甲状旁腺激素受体的作用 破骨细胞发育和功能中的受体。组织形态计量学 尿骨吸收标志物和原位杂交将是 用于评估破骨细胞发育和功能的异常。 两种Cre-lox小鼠的比较及对小鼠缺失的利用 PTH基因将阐明不同水平的成骨细胞的作用 以及甲状旁腺素和甲状旁腺素rP的相关作用。这些研究将 使我们更好地理解 甲状旁腺素在骨骼上的作用，并可能导致甲状旁腺激素样药物在 治疗骨质疏松症。