Novel Molecular and Cellular Mechanisms for Osteoanabolic Action of Parathyroid Hormone

项目总结/摘要 骨质疏松症困扰着老年人群，并且是由于成骨细胞与骨细胞之间的平衡被破坏而导致的。 骨形成和骨吸收。间歇性甲状旁腺激素（PTH）每日注射 增加骨形成，而持续PTH导致骨吸收。然而， PTH的间歇给药增加骨量仍然知之甚少;描绘这些 这些机制可以使基于PTH的骨质疏松症治疗的改进成为可能。合成代谢PTH对 骨的生长主要由Gs/cAMP信号级联和经典的β-连环蛋白途径介导， 而Gq/PLC激活可能拮抗这些骨合成代谢作用。此外，其他 包括PTH刺激的PLD活性、ERK 1/2活化和PI 3 K/Akt信号传导的信号传导途径也影响 PTH在骨中的合成代谢作用。我们已经获得了大量的数据表明PTHR与 β-连环蛋白显著抑制PTHR信号传导的合成代谢作用， 细胞渗透肽构成了提高体内甲状旁腺激素功效的可行治疗方法。的 该提案的主要目标是描述促进/抑制PTHR信号传导的多个要素， PTH对骨的合成代谢作用。我们将检验PTHR与β-连环蛋白分离的假设， 随后的运输诱导不同的信号传导途径，介导PTH的合成代谢作用， 骨，并且促进PTHR-β-连环蛋白解离的破坏肽具有促合成代谢治疗作用。 体内效用提出了三个目标来检验这一假设。在目标1中，我们将阐明 β-连环蛋白与PTHR偶联导致PTHR的初始偏向信号传导，以及PTHR运输和 β-连环蛋白易位在维持合成代谢PTH信号传导中的作用。目标2将定义干扰肽的作用 调节多种PTHR信号通路。在目标3中，我们将直接评估β- 连环蛋白与PTHR在体外和体内增加成骨细胞骨形成，减少破骨细胞骨吸收。 vivo.成功完成拟议的研究将有助于更好地了解分子 以及介导PTH对骨作用的细胞机制，并提出一种新的治疗方式， 改善基于PTH骨质疏松症治疗。

Project Summary/Abstract Osteoporosis afflicts the elderly population and results from a disruption of the balance between osteoblastic bone formation and osteoclastic bone resorption. Intermittent parathyroid hormone (PTH) by daily injection increases bone formation, whereas continuous PTH causes bone resorption. However, the mechanisms by which intermittent administration of PTH increases bone mass remain poorly understood; delineation of these mechanisms could enable a refinement of PTH-based osteoporosis treatment. The anabolic PTH effects on bone are mediated mostly by the Gs/cAMP signaling cascades and the canonical beta-catenin pathway that is independent of Wnt, whereas Gq/PLC activation may antagonize these osteoanabolic actions. In addition, other signaling pathways including PTH-stimulated PLD activity, ERK1/2 activation and PI3K/Akt signaling also affect the anabolic PTH actions in bone. We have obtained considerable data suggesting the interaction of PTHR with beta-catenin significantly constrains the anabolic effect of PTHR signaling, and disruption of this interaction with a cell-permeable peptide constitutes a viable therapeutic approach for improving the efficacy of PTH in vivo. The major goal of this proposal is to delineate the multiple elements of PTHR signaling that promote/restrain the anabolic effects of PTH on bone. We will test the hypothesis that PTHR dissociates from beta-catenin and subsequent trafficking of each induces distinct signaling pathways that mediate the anabolic action of PTH in bone, and that a disruptor peptide that promotes PTHR-beta-catenin dissociation has pro-anabolic therapeutic utility in vivo. Three aims are proposed to test this hypothesis. In aim 1, we will elucidate mechanisms whereby beta-catenin coupling to PTHR elicits initial biased signaling of the PTHR, and the role of PTHR trafficking and beta-catenin translocation in sustaining anabolic PTH signaling. Aim 2 will define the role of the disruptor peptide in regulating multiple PTHR signaling pathways. In aim 3, we will directly assess whether disruption of beta- catenin with PTHR increases osteoblast bone formation and reduces osteoclast bone resorption in vitro and in vivo. Successful completion of the proposed research will contribute to a better understanding of the molecular and cellular mechanisms mediating the actions of PTH on bone and advance a novel therapeutic modality to improve PTH-based treatment for osteoporosis.