Parathyroid Hormone Signaling in Bone Cells

骨细胞中的甲状旁腺激素信号传导

• 批准号: 6912799
• 负责人: ALESSANDRO BISELLO
• 金额: $ 21.1万
• 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/6912799
• 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，在美国，有超过1000万男性患有骨质疏松症，有2000万男性面临骨质疏松骨折的风险。动物和人类研究表明，当低剂量以间歇性地给药时，PTH和PTH相关蛋白（PTHRP）都有效地刺激了骨形成。 PTH和PTHRP的骨合成代谢活性与在成骨细胞和骨髓基质细胞中表达的1型PTH/PTHRP受体（PTHI RC）的能力有关。 PTH1 RC耦合到几种信号通路，导致蛋白激酶A（PKA），PKC和有丝分裂原激活的蛋白激酶ERK1和ERK2的激活。尽管GS/CAMP/PKA信号通路似乎是刺激骨骼中合成代谢反应的必要，但最近的研究已经确定了PKC和Beta-arrestin2在PTH 1 RC功能脱敏中的合并作用。该研究提案的中心假设是，对PTH和PTHRP的细胞反应不仅取决于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-arret蛋白2络合物的其他相互作用。具体而言，我们假设GS/CAMP/PKA途径的连续和选择性激活将诱导基因，蛋白质和细胞反应的表达与骨骼上的合成代谢活性相关。非敏感的PTHRP类似物的开发显示出选择性和持续的cAMP信号传导，可以直接检验该假设。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在成骨细胞和基质细胞中介导PTH 1RC信号转导和细胞运输中的作用； 3）确定通过成骨细胞和基质细胞对cAMP信号传导的选择性和连续刺激对基因/蛋白质表达的影响； 4）确定选择性和连续刺激cAMP信号传导对成骨细胞和基质细胞增殖和凋亡的影响。这些研究将提高对PTH和PTHRP细胞作用的分子机制的理解，并可能导致基于PTH/PTHRP的新型合成代谢化合物的发展。