OSTEOBLAST SPECIFIC ABLATION OF THE PTH/PTHRP RECEPTOR

甲状旁腺激素（PTH）是最好的特点的小团体 增加骨形成并可能成为治疗的一部分 对于能够恢复该患者正常骨量的骨质疏松症 组甲状旁腺激素的作用是由一个共同的 PTH和PTH相关蛋白（PTHrP）的受体，并涉及 增加骨形成和骨吸收。这个目标 我们的建议是，在体内评估PTH和PTH~P的作用， 调节成骨细胞和破骨细胞的发育和功能， 特异性地从所述细胞中缺失PTH/PTHrP受体基因， 成骨细胞谱系。第一个目标是建立小鼠品系 选择性缺失PTH/PTHrP受体基因仅在成骨细胞中， 不同程度的成熟。 cre-lox系统将用于 产生成骨细胞中缺失PTH/PTHrP受体基因的小鼠， 表达α 1（I）胶原蛋白基因启动子， 骨钙素基因启动子。 第二个目标是评估 PTH/PTHrP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。 两种类型的cre-lox小鼠的比较将阐明相对的 不同成熟度的成骨细胞的作用。 老鼠错过了 PTH基因将被用来评估PTH和PTHrP的个体作用， 激活PTH/PTHrP受体以控制成骨细胞发育， 功能 第三个目标是评估PTH/PTHrP的作用 受体在破骨细胞发育和功能中的作用。组织形态计量学， 尿中骨吸收标记物和原位杂交将被 用于评估破骨细胞发育和功能的异常。 两种cre-lox小鼠的比较及缺失小鼠的使用 PTH基因将阐明不同水平成骨细胞的作用， 以及PTH和PTHrP的相对作用。这些研究将 从而更好地理解潜在的冲突行为， PTH对骨的影响，并可能导致更有效地使用PTH样药物， 骨质疏松症的治疗

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.