Actions of Parathyroid Hormone(PTH)/PTH related-peptide receptor in Osteocytes in

骨细胞占所有骨细胞的90%以上，但对其功能知之甚少 或者是系统激素参与调节它们的活动。这些细胞 存在于骨矿化基质深处的腔隙中， 并通过位于末端的缝隙连接与成骨细胞和破骨细胞连接 在骨中穿过隧道（管状体）的长的细胞质突起。 最近的研究支持这样的理论，即骨细胞起着主要的机械感觉作用， 由此它们被剪切力和拉伸力刺激以产生局部细胞因子， 体液因子（如NO和PGE 2）和增加少数基因（如 如c-fos和IGF-1）。甲状旁腺激素（PTH），一种由84个氨基酸组成的多肽， 由甲状旁腺，是一个主要的生理调节钙，磷， 骨骼稳态，临床上，是唯一可用的合成代谢剂治疗 骨质疏松该激素通过激活G蛋白对靶细胞发挥作用 偶联受体，1型PTH/PTHrP受体（PPR），在骨中高度表达 和肾脏。成骨细胞谱系的细胞是骨中PTH作用的关键靶点， 最近的证据表明，骨细胞可能是重要的合成代谢作用， PTH。本项目的主要目标是了解PPR在骨细胞中的作用， 确定这些细胞在介导激素对骨的影响中的作用。到 为了解决这些问题，PPR表达特异性消除的小鼠， 将产生骨细胞。10 Kb-DMP 1启动子，在 骨细胞，将驱动他莫昔芬诱导的Cre表达的细胞，其中PPR 基因两侧是lox-P位点。此外，非诱导型10 KbDMP 1-Cre和 将使用8 KbDMP 1-Cre模型，并由我们的合作者提供。这 动物模型将使人们更好地了解甲状旁腺素对骨骼的作用， 指导新型治疗剂的开发。这些结果可能具有重要意义 对治疗骨疾病如甲状旁腺功能亢进、骨质疏松症 和肾性骨营养不良。

Osteocytes comprise over 90% of all bone cells, yet little is known of their function(s) or of the involvement of systemic hormones in regulating their activity. These cells reside in the lacunae deep within the mineralized matrix of bone and communicate with one another and with osteoblasts and osteoclasts via gap junctions located at the ends of long cytoplasmic processes that course through tunnels (cannalicula) in the bone. Recent studies support the theory that osteocytes play a major ¿mechanosensory¿ role, whereby they are stimulated by shear and stretch forces to produce local cytokines or humoral factors (such as NO and PGE2) and to increase expression of few genes (such as c-fos and IGF-1). Parathyroid hormone (PTH), an 84-amino-acid polypeptide secreted by the parathyroid glands, is a major physiologic regulator of calcium, phosphorous and skeletal homeostasis and, clinically, is the only available anabolic agent to treat osteoporosis. The hormone exerts its effects on target cells via activation of a G-protein coupled receptor, the type-1 PTH/PTHrP receptor (PPR),that is highly expressed in bone and kidney. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. The main goal of this project is to understand the role of PPRs in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone on bone. To address these questions, mice in which PPR expression is specifically ablated in osteocytes will be generated. The 10Kb-DMP1 promoter, active specifically in osteocytes, will drive a Tamoxifen-inducible Cre expression in cells in which the PPR gene is flanked by lox-P sites. In addition a non-inducible 10KbDMP1-Cre and the 8KbDMP1-Cre models will be used and will be provided by our collaborators. This animal models will enable enhanced understanding of PTH action on bone and could direct the development of novel therapeutic agents. These results could have significant implications for therapy of bone disorders such as hyperparathyroidism, osteoporosis and renal osteodystrophy.