PATHOPHYSIOLOGY OF OSTEOPOROSIS

骨质疏松症的病理生理学

基本信息

批准号：
7650701
负责人：
SUNDEEP KHOSLA
金额：
$ 39.89万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650701
关键词：
Acute Age Age-Related Bone Loss Aging Antibodies Apoptosis Attenuated B-Lymphocytes Biological Assay Bone Marrow Bone Morphogenetic Proteins Bone Resorption Cells Complement Conditioned Culture Media Coupled Data Defect Disease Dose Elderly Elderly woman Equation Estrogen Receptors Estrogens Flow Cytometry Follicle Stimulating Hormone Functional disorder Funding Gender Gene Expression Gene Proteins Genes Human Impairment In Vitro Interleukin-1 Knock-in Mouse Lead Ligands Measurement Mediating Menopause Messenger RNA Methods Modeling Mus Nuclear Osteoblasts Osteoclasts Osteogenesis Osteoporosis Pathway interactions Phase Physiology Polymerase Chain Reaction Population Postmenopausal Osteoporosis Postmenopause Premenopause Production Proteins Research Personnel Response Elements Rodent Model Role Signal Pathway Signal Transduction Skeleton Source TNFSF11 gene Techniques Testing Thick Time Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Wild Type Mouse Woman Work age effect age related aged aging population base bone bone loss bone metabolism bone morphogenetic protein 6 bone turnover clinically relevant cost gonad function human data in vivo indexing lymphoid enhancer-binding factor 1 men mouse model new therapeutic target novel novel strategies osteoblast differentiation prevent protein expression receptor senescence

项目摘要

Estrogen (E) deficiency is the major cause of postmenopausal osteoporosis. Thus, understanding the mechanisms by which E regulates bone metabolism is critical for developing novel approaches to prevent and treat this disorder. This project focuses on better defining key, unresolved issues regarding E action on bone in women. While previous studies have demonstrated that E deficiency is associated with increased RANKL expression by osteoblastic cells, a major unresolved issue regarding the increase in bone resorption in women following the menopause is whether increased resorption is solely due to E deficiency or is augmented by the concomitant rise in circulating follicle-stimulating hormone (FSH) levels. Thus, in Specific Aim 1 we will test the hypothesis that FSH directly regulates bone resorption independently of E. In addition to regulating bone resorption, it is clear that E also has important effects on maintaining bone formation. In Specific Aims 2 and 3, we focus on defining mechanisms for the age-related decrease in bone formation and the role of E deficiency in mediating this decrease. We will couple two novel in vivo human experimental paradigms with methods we have established to examine gene expression in highly purified bone marrow osteoblastic cells. Using quantitative polymerase chain reaction assays complemented by assessment of key functional and protein measurements by flow cytometry, we will test the hypothesis that there are both Edependent and E-independent defects in bone formation in aging women. In Specific Aim 2, we will test whether the decrease in bone formation we have previously observed following acute E deficiency in women is associated with a decrease in markers of Wnt/BMP signaling and/or production and in other genes related to bone formation by osteoblastic cells. In Specific Aim 3, we will test the hypothesis that there is an Eindependent defect in bone formation in elderly women and identify potential novel mechanisms for this agerelated impairment in bone formation. Collectively, these studies will lead to a better understanding of E action on bone, and are highly clinically relevant since they may identify new therapeutic targets to prevent and treat osteoporosis.

雌激素（E）缺乏是绝经后骨质疏松症的主要原因。因此，了解 E调节骨骼代谢的机制对于开发新的方法至关重要并治疗这种疾病。该项目着重于更好地定义有关E的键，未解决的问题女性的骨头。虽然先前的研究表明E缺乏症与增加有关成骨细胞表达RANKL表达，这是一个关于骨吸收增加的主要未解决的问题在更年期之后的妇女中，增加的吸收是否仅是由于E缺乏症还是循环促卵泡激素（FSH）水平的伴随上升增强。因此，具体目的1我们将测试FSH直接调节骨吸收的假设。为了调节骨吸收，很明显，E对维持骨形成也有重要影响。在具体目的2和3，我们专注于定义与年龄相关的骨形成减少的机制和 E缺乏在介导这种减少中的作用。我们将在人体实验中撰写两本小说我们已经建立了使用方法来检查高纯化骨髓中基因表达的范例成骨细胞。使用定量聚合酶链反应测定法，并通过评估通过流式细胞术测量关键功能和蛋白质测量，我们将检验以下假设。衰老女性的骨形成中的电子非依赖性缺陷。在特定目标2中，我们将测试在女性急性E缺乏之后，我们以前观察到骨形成的减少是否减少与Wnt/BMP信号传导和/或生产以及其他基因相关的WNT/BMP信号的标记降低有关由成骨细胞形成骨骼。在特定目标3中，我们将检验以下假设老年妇女的骨骼形成缺陷，并确定了这种变性的潜在新机制骨形成的损害。总的来说，这些研究将导致对E的更好理解对骨骼的作用，并且在临床上具有很高的相关性，因为它们可能会确定新的治疗靶标的并治疗骨质疏松症。