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

描述（申请人提供）：骨细胞占所有骨细胞的90%以上，但对其功能或全身激素参与调节其活性的情况知之甚少。这些细胞位于骨矿化基质深处的陷窝中，并通过位于长细胞质突起末端的间隙连接彼此通信，并与成骨细胞和破骨细胞通信，所述长细胞质突起穿过骨中的隧道（小管）。最近的研究支持这样的理论，即骨细胞发挥主要的“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或体液因子（如NO和PGE 2）并增加少数基因（如c-fos和IGF-1）的表达。甲状旁腺激素（PTH）是由甲状旁腺分泌的84个氨基酸的多肽，是钙、磷和骨骼稳态的主要生理调节剂，并且是临床上唯一可用的治疗骨质疏松症的合成代谢剂。该激素通过激活G蛋白偶联受体（1型PTH/PTHrP受体（PPR））对靶细胞发挥作用，该受体在骨骼和肾脏中高度表达。成骨细胞系是PTH在骨中作用的关键靶点，最近的证据表明骨细胞在PTH的合成代谢作用中可能是重要的。该项目的主要目标是了解PPR在骨细胞中的作用，并确定这些细胞在介导激素对骨的影响中的作用。为了解决这些问题，将产生骨细胞中PPR表达特异性消除的小鼠。10 Kb-DMP 1启动子在骨细胞中特异性地具有活性，将在PPR基因侧翼为lox-P位点的细胞中驱动他莫昔芬诱导的Cre表达。此外，将使用非诱导型10 KbDMP 1-Cre和8 KbDMP 1-Cre模型，并由我们的合作者提供。这种动物模型将能够增强对PTH对骨作用的理解，并可指导新型治疗剂的开发。这些结果可能对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的治疗具有重要意义。公共卫生相关性：如果成功的话，这一建议将显着推进我们的PTH和PTH受体在骨细胞中的作用的知识，并进一步提高我们对这些细胞的理解。这些研究的结果可能对骨疾病如甲状旁腺功能亢进、骨质疏松和肾性骨营养不良的治疗有重要意义。因此，它的相关性是高的骨骼生物学。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: If successful this proposal will significantly advance our knowledge of the role of PTH and the PTH receptors in osteocytes and further enhance our understanding of these cells. Results derived from the studies proposed could have significant implications for therapy of bone disorders such as hyperparathyroidism, osteoporosis and renal osteodystrophy. Thus, its relevance is high for skeletal biology.