Parathyroid Hormone Signaling in Bone Cells

骨细胞中的甲状旁腺激素信号传导

• 批准号: 6603881
• 负责人: ALESSANDRO BISELLO
• 金额: $ 21.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603881
• 关键词: apoptosis; arrestins; biological signal transduction; bone development; bone marrow; bone metabolism; cell differentiation; cell line; cell proliferation; cyclic AMP; endocytosis; gene expression; hormone receptor; hormone regulation /control mechanism; laboratory mouse; osteoblasts; osteocytes; osteoporosis; parathyroid hormone related protein; parathyroid hormones; protein kinase A

DESCRIPTION (provided by applicant): Osteoporosis is the most common human bone disorder. It is estimated that more than 10 million women and men in the United States have osteoporosis and 20 million more are at risk for osteoporotic fractures. Animal and human studies have shown that, when administered intermittently at low doses, both PTH and PTH-related protein (PTHrP) effectively stimulate bone formation. The bone anabolic activity of PTH and PTHrP is associated with their capacity to stimulate the type 1 PTH/PTHrP receptor (PTHI Rc), expressed in both osteoblasts and bone marrow stromal cells. PTH1 Rc is coupled to several signaling pathways, leading to activation of protein kinase A (PKA), PKC and mitogen-activated protein kinases ERK1 and ERK2. While the Gs/cAMP/PKA signaling pathway seems to be necessary, and possibly sufficient, to stimulate an anabolic response in the skeleton, recent studies have established the combined actions of PKC and beta-arrestin2 in the desensitization of PTH 1 Rc function. The central hypothesis of this research proposal is that the cellular responses to PTH and PTHrP depend not only on PTH1 Rc-mediated signal transduction, but also on additional interactions with arrestins, endocytosis and cellular trafficking of ligand/receptor beta-arrestin2 complexes. Specifically, we hypothesize that continuous and selective activation of the Gs/camp/PKA pathway will induce expression of genes, proteins and cellular responses associated with the anabolic activity on bone. The development of non-desensitizing PTHrP analogs displaying selective and sustained CAMP signaling permits the direct testing of this hypothesis. We therefore propose to: 1) identify specific interactions between PTH1 Rc and beta-arrestin2; 2) determine the role of beta-arrestin2 in mediating PTH 1Rc signal transduction and cellular trafficking in osteoblasts and stromal cells; 3) determine the effect of selective and continuous stimulation of cAMP signaling on gene/protein expression by osteoblasts and stromal cells; 4) determine the effect of selective and continuous stimulation of cAMP signaling on osteoblasts and stromal cells proliferation and apoptosis. These studies will advance the understanding of the molecular mechanisms underlying the cellular actions of PTH and PTHrP and may lead to the development of novel PTH/PTHrP-based anabolic compounds.

描述（由申请人提供）：骨质疏松症是最常见的人类骨骼疾病。据估计，美国有超过 1000 万女性和男性患有骨质疏松症，还有 2000 万有骨质疏松性骨折的风险。动物和人类研究表明，当以低剂量间歇给药时，PTH 和 PTH 相关蛋白 (PTHrP) 都能有效刺激骨形成。 PTH 和 PTHrP 的骨合成代谢活性与其刺激 1 型 PTH/PTHrP 受体 (PTHI Rc) 的能力相关，该受体在成骨细胞和骨髓基质细胞中表达。 PTH1 Rc 与多种信号传导途径偶联，导致蛋白激酶 A (PKA)、PKC 和丝裂原激活蛋白激酶 ERK1 和 ERK2 的激活。虽然 Gs/cAMP/PKA 信号通路对于刺激骨骼中的合成代谢反应似乎是必要的，而且可能是充分的，但最近的研究已经确定了 PKC 和 β-arrestin2 在 PTH 1 Rc 功能脱敏中的联合作用。本研究提案的中心假设是，细胞对 PTH 和 PTHrP 的反应不仅取决于 PTH1 Rc 介导的信号转导，还取决于与抑制蛋白、内吞作用和配体/受体 β-arrestin2 复合物的细胞运输的其他相互作用。具体来说，我们假设 Gs/camp/PKA 途径的连续和选择性激活将诱导与骨合成代谢活性相关的基因、蛋白质和细胞反应的表达。显示选择性和持续 CAMP 信号传导的非脱敏 PTHrP 类似物的开发允许直接测试这一假设。因此，我们建议：1）确定 PTH1 Rc 和 beta-arrestin2 之间的特定相互作用； 2)确定β-arrestin2在介导成骨细胞和基质细胞中PTH 1Rc信号转导和细胞运输中的作用； 3)确定选择性和持续刺激cAMP信号对成骨细胞和基质细胞基因/蛋白质表达的影响； 4)确定选择性和持续刺激cAMP信号对成骨细胞和基质细胞增殖和凋亡的影响。这些研究将增进对 PTH 和 PTHrP 细胞作用分子机制的理解，并可能导致新型 PTH/PTHrP 合成代谢化合物的开发。