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(S) 或者系统激素参与调节它们的活动。这些细胞 驻留在骨骼矿化基质深处的陷窝中，并与 通过位于末端的缝隙连接与成骨细胞和破骨细胞相互连接 长的细胞质突起，穿过骨骼中的隧道(小管)。 最近的研究支持这样的理论，即骨细胞发挥着主要的机械感觉作用， 在剪切力和拉伸力的刺激下，它们产生局部细胞因子或 体液因子(如NO和PGE2)和增加少数基因(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 甲状旁腺是钙、磷和钙的主要生理调节器。 骨骼动态平衡，临床上是唯一可以治疗的合成代谢药物。 骨质疏松。这种激素通过激活G蛋白对靶细胞起作用 偶联受体，1型甲状旁腺激素/甲状旁腺素受体(PPR)，在骨组织中高表达 还有肾脏。成骨细胞系的细胞是甲状旁腺素在骨中作用的关键靶点，并且 最近的证据表明，骨细胞可能在骨钙素的合成代谢作用中起重要作用。 PTH。这个项目的主要目标是了解Pprs在骨细胞中的作用，并 确定这些细胞在调节激素对骨骼的影响中的作用(S)。至 为了解决这些问题，在PPR表达被特异性消融的小鼠中 就会产生骨细胞。10kb-DMP1启动子，特异性地激活于 骨细胞，将驱动他莫昔芬诱导的Cre在细胞中的表达 基因的两侧是lox-P位点。此外，非诱导型10KbDMP1-CRE和 将使用8KbDMP1-CRE模型，并由我们的合作者提供。这 动物模型将使人们能够更好地了解甲状旁腺素对骨骼的作用，并可能 指导新型治疗剂的开发。这些结果可能会有重大意义 对甲状旁腺功能亢进症、骨质疏松症等骨病治疗的启示 和肾性骨病。

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.