NOVEL REGULATORY MECHANISMS CONTROLLING BONE REPAIR AND OSTEOPOROSIS

控制骨修复和骨质疏松的新型调节机制

基本信息

批准号：
7447840
负责人：
Peter A Friedman
金额：
$ 21.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7447840
关键词：
Adaptor Signaling Protein Affect Age-Years American Animals Binding Proteins Biological Models Bone Growth Bone Marrow Bone Regeneration Cell surface Cells Cessation of life Deterioration Disease Endocrine Estradiol Estrogen Replacements Estrogens Event Female Fracture Genetic Goals Gonadal Hormones Hip Fractures Hip region structure Hormonal Hormones Human Intervention Knockout Mice Lead Left Measures Mediating Modeling Nutritional Osteoblasts Osteoclasts Osteoporosis Parathyroid Hormone Receptor Parathyroid Hormones Peptides Postmenopausal Osteoporosis Predisposition Publishing RNA Synthesis Induction Rat Cell Line Regulation Research Design Response Elements Risk Series Skeletal system Skeleton Testing Testosterone Therapeutic Intervention Thinking Transactivation Vertebral column Work Wrist adapter protein base bone bone cell bone health bone loss demineralization ezrin hormone regulation hormone resistance human PTH protein lifetime risk malignant breast neoplasm men novel older women prevent protein 50 kDa protein expression receptor research study response theories

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis is a disease that is characterized by low bone mass that results in insidious deterioration of the skeleton leaving it fragile and vulnerable to fracture. Osteoporosis is due to multiple genetic, hormonal, nutritional, and physical factors that act alone or together to diminish skeletal integrity. Estrogen replacement blunts the loss of bone by blocking osteoclast-mediated bone demineralization. In this setting, parathyroid hormone (PTH) is able to mediate bone growth. We recently made a series of observations that suggest another potentially important mechanism by which estrogen deficiency may contribute to osteoporosis. Specifically, we found that amino-terminally truncated PTH fragments that are thought to be inactive promoted rapid internalization of the PTH receptor (PTH1R) in a cell-specific manner in bone. These otherwise biologically inactive PTH fragments reduced the abundance of PTH1R on the cell surface without first activating the receptor. This uncoupling of PTH1R activation and inactivation is due to the presence of a cytoplasmic adaptor protein, termed EBP50 (ezrin-binding protein, 50 kDa). EBP50 contains an estrogen response element. Experimental animals lacking EBP50 have osteopenia and develop osteoporosis. We hypothesize that estrogens increase EBP50 expression, thereby protecting the osteoblast PTH1R against the inactivating effects of PTH fragments. The Specific Aims of this project are: (1) To examine gonadal hormone regulation of EBP50, and (2) to determine if estrogen induction of EBP50 expression contributes to restoring the anabolic action of PTH on bone. The effects of gonadal hormones on EBP50 expression will be determined in osteoblastic human and rat cell lines. The second group of experiments consists of two parts. In the first, ectopic ossicles prepared from bone marrow of EBP50-null mice will be used as a model system to analyze the effects of PTH and estrogens on bone, independent of systemic effects or the donor animal. The second part will examine the effects of estradiol administration alone or in combination with PTH on restoring bone in ovariectomized EBP50-null mice. The proposed studies will lead to a better understanding of the hormonal events that impact bone health and importantly influence the response to bone loading. Novel predictive measures of fragility and potential avenues for therapeutic intervention may be developed. The goal of these new studies is to characterize how the effect of female hormones on bone may be regulated by a certain adapter protein. The long-term objective is to identify novel compounds that can be used to treat post-menopausal osteoporosis.

描述（由申请人提供）：骨质疏松症是一种疾病，其特征是骨骼低，导致骨骼的阴险恶化，使其脆弱且容易受到骨折的影响。骨质疏松症是由于多种遗传，荷尔蒙，营养和物理因素引起的，它们单独起作用或一起起作用以减少骨骼完整性。雌激素替代通过阻止破骨细胞介导的骨骼脱矿化来钝化骨骼的丧失。在这种情况下，甲状旁腺激素（PTH）能够介导骨骼生长。最近，我们进行了一系列观察结果，提出了另一种潜在的重要机制，雌激素缺乏可能导致骨质疏松症。具体而言，我们发现被认为是不活跃的氨基末端截断的PTH片段以骨骼特异性方式促进了PTH受体（PTH1R）的快速内在化。这些否则在生物学上不活跃的PTH片段可降低细胞表面上的PTH1R的丰度，而无需先激活受体。 PTH1R激活和灭活的这种解偶联是由于存在胞质衔接蛋白的存在，称为EBP50（Ezrin结合蛋白，50 kDa）。 EBP50包含雌激素反应元件。缺乏EBP50的实验动物患有骨质减少症并发展骨质疏松症。我们假设雌激素会增加EBP50的表达，从而保护成骨细胞PTH1R免受PTH片段的灭活作用。该项目的具体目的是：（1）检查EBP50的性腺激素调节，以及（2）确定EBP50表达的雌激素诱导是否有助于恢复PTH的合成代谢作用。性腺激素对EBP50表达的影响将在成骨细胞和大鼠细胞系中确定。第二组实验由两个部分组成。首先，由EBP50无效小鼠的骨髓制备的异位小骨将用作模型系统，以分析PTH和雌激素对骨骼的影响，与全身性效应或供体动物无关。第二部分将检查单独或与PTH结合使用雌二醇对卵巢骨切除的EBP50-NULL小鼠的骨骼的影响。拟议的研究将使对影响骨骼健康的激素事件有更好的了解，并重要地影响对骨负荷的反应。可以开发出脆性和潜在途径的新型预测性测量。这些新研究的目的是表征女性激素对骨骼的影响如何受到某种衔接蛋白的调节。长期目标是鉴定可用于治疗绝经后骨质疏松症的新型化合物。