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

• 批准号: 7252994
• 负责人: Peter A Friedman
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/7252994
• 关键词: NOVEL; REGULATORY; MECHANISMS; CONTROLLING; BONE

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）：骨质疏松症是一种以骨量低为特征的疾病，会导致骨骼的潜在恶化，使其变得脆弱且容易骨折。骨质疏松症是由多种遗传、激素、营养和身体因素造成的，这些因素单独或共同作用会降低骨骼的完整性。雌激素替代通过阻止破骨细胞介导的骨脱矿来减少骨质流失。在这种情况下，甲状旁腺激素（PTH）能够介导骨骼生长。我们最近进行的一系列观察结果表明，雌激素缺乏可能导致骨质疏松症的另一个潜在重要机制。具体来说，我们发现被认为无活性的氨基末端截短的 PTH 片段以细胞特异性方式促进骨中 PTH 受体 (PTH1R) 的快速内化。这些原本没有生物活性的 PTH 片段减少了细胞表面 PTH1R 的丰度，而无需首先激活受体。 PTH1R 激活和失活的这种解偶联是由于细胞质接头蛋白的存在，称为 EBP50（埃兹蛋白结合蛋白，50 kDa）。 EBP50 含有雌激素反应元件。缺乏EBP50的实验动物会出现骨质减少并出现骨质疏松症。我们假设雌激素增加 EBP50 表达，从而保护成骨细胞 PTH1R 免受 PTH 片段的失活作用。该项目的具体目标是：(1) 检查 EBP50 的性腺激素调节，以及 (2) 确定雌激素诱导 EBP50 表达是否有助于恢复 PTH 对骨骼的合成代谢作用。性腺激素对 EBP50 表达的影响将在人和大鼠成骨细胞系中确定。第二组实验由两部分组成。首先，从 EBP50 缺失小鼠的骨髓中制备的异位小骨将被用作模型系统来分析 PTH 和雌激素对骨骼的影响，而与全身效应或供体动物无关。第二部分将检查雌二醇单独给药或与 PTH 联合给药对卵巢切除 EBP50 缺失小鼠骨恢复的影响。拟议的研究将有助于更好地了解影响骨骼健康的激素事件，并重要地影响对骨负荷的反应。可以开发新的脆弱性预测措施和治疗干预的潜在途径。这些新研究的目的是确定女性激素对骨骼的影响如何通过某种接头蛋白进行调节。长期目标是确定可用于治疗绝经后骨质疏松症的新化合物。