Purinergic Regulation of Bone Metabolism

骨代谢的嘌呤能调节

基本信息

批准号：
8698897
负责人：
BRUCE Neil CRONSTEIN
金额：
$ 13.03万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8698897
关键词：
5&apos -Nucleotidase Address Adenine Nucleotides Adenosine Adenosine A1 Receptor Adenosine A2 Receptors Agonist Alkaline Phosphatase Animal Model Animals Binding Biochemical Bone Marrow Bone Resorption Bone remodeling Catabolism Cell Culture Techniques Cells Child Development Disease Elderly Enzymes Event Family member Fracture G-Protein-Coupled Receptors Generations Giant Cells Heart Rate Human Hypoxia In Vitro Inflammation Inflammatory Injury Knock-out Knockout Mice Laboratories Lead Ligation Liquid substance Mediating Mesenchymal Modeling Molecular Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteoporosis prevention Parkinson Disease Pathology Physiological Play Postmenopausal Osteoporosis Predisposition Process Production Proteolysis Public Health Purine Nucleosides Purinergic P1 Receptors Regulation Rheumatoid Arthritis Role Signal Transduction Stress TRAF6 gene Techniques Tissues Ubiquitination Vasodilation adenosine deaminase deficiency aging population base bone bone loss bone mass bone metabolism cell type extracellular human disease in vivo inhibitor/antagonist macrophage monocyte neutrophil new therapeutic target nucleoside triphosphatase osteoclastogenesis peripheral blood phosphoric diester hydrolase prevent pyrophosphatase receptor response

项目摘要

The purine nucleoside adenosine regulates such physiologic functions as heart rate, vasodilation and inflammation and receptors for adenosine have been targeted for such diverse conditions as Parkinson's Disease and, indirectly, Rheumatoid Arthritis. Few studies have addressed the role of adenosine and its receptors in bone metabolism despite clear demonstrations of bony pathology in children with marked elevations in adenosine levels due to adenosine deaminase deficiency. We had previously observed that adenosine A1 receptors regulate the stimulated formation of multinucleated giant cells by cultured human peripheral blood monocytes and therefore determined whether adenosine A1 receptors also regulated formation of osteoclasts, a related form of multinucleated giant cell. We were surprised to find, in preliminary studies, that either blockade or knockout of adenosine receptors prevents osteoclast formation in vitro. Moreover, adenosine A1 receptor knockout mice have increased bone formation in vivo and adenosine receptor blockade blocks bone loss in ovariectomized mice. Preliminary studies further demonstrate that blockade of adenosine A1 receptors in vitro alters signaling events required for osteoclastogenesis. We propose four aims to confirm and expand on our preliminary findings. In the first aim we will examine the role of adenosine and adenosine A1 receptors in osteoclast function and bone remodeling and confirm and expand on our preliminary studies. The second aim is to determine the biochemical basis for adenosine generation during bone remodeling using animals deficient in the enzymes that convert extracellular adenine nucleotides to adenosine (NPP-1, TNAP, CD39 and CD73). The third aim is to dissect the mechanism by which adenosine A1 receptors modulate the formation and function of osteoclasts in vitro using a combination of molecular techniques and inhibitors of signaling enzymes. The demonstration that adenosine A1 receptors play a critical role in regulating the formation and function of osteoclasts suggests a novel therapeutic target for the treatment of disorders characterized by osteoclast-mediated bone resorption. One of the most pressing public health problems for the aging population is the increasing fragility and brittleness of bones, osteoporosis; brittle and de-mineralized bones are much more susceptible to fractures which are a major problem for the elderly. We have discovered that adenosine, a substance which is present in almost all bodily fluids, can bind to a receptor which is critical for formation and function of osteoclasts, the cells that break down bone. We propose to investigate the role of these adenosine receptors in regulating bone remodeling and the mechanism by which adenosine and its receptor modulate osteoclast function. The studies proposed here are directly relevant to human disease and may lead to the rapid development of new therapies for the treatment and prevention of osteoporosis and the resulting susceptibility to fractures that is so common in the elderly.¿

嘌呤核外侧腺苷调节这种生理功能为心率，血管舒张，炎症和腺苷的接收器已被针对此类帕金森氏病以及间接的类风湿关节炎等不同的疾病。很少研究已经解决了腺苷及其受体在骨代谢中的作用尽管清楚地证明了具有明显高度的儿童的骨病理学由于腺苷脱氨酶缺乏而引起的腺苷水平。我们以前已经观察到腺苷A1受体调节多核巨人的刺激形成细胞通过培养的人类外周血单核细胞，因此确定是否确定腺苷A1受体还调节破骨细胞的形成，一种相关形式的形式多核巨细胞。在初步研究中，我们很惊讶地发现腺苷受体的封锁或敲除可以在体外阻止破骨细胞形成。此外，腺苷A1受体基因敲除小鼠体内骨形成增加腺苷接收器阻断阻塞卵巢切除小鼠的骨质流失。初步的研究进一步表明，腺苷A1受体的封锁在体外改变破骨细胞生成所需的信号事件。我们提出了四个目标，以确认和扩展我们的初步发现。在第一个目标中，我们将研究破骨细胞功能中的腺苷和腺苷A1受体重塑并确认并扩展我们的初步研究。第二个目标是确定骨骼中腺苷产生的生化基础使用缺乏转化细胞外腺嘌呤的酶的动物进行重塑核苷酸到腺苷（NPP-1，TNAP，CD39和CD73）。第三个目的是剖析腺苷A1受体调节形成和骨细胞在体外的功能，结合了分子技术和信号传导酶的抑制剂。腺苷A1受体发挥的演示在确定破骨细胞的形成和功能中的关键作用表明了一种新颖以破骨细胞介导的特征的疾病治疗的治疗靶标骨骼分辨率。对于老龄化人群而言，最紧迫的公共卫生问题之一是增加骨骼的脆弱性和脆性，骨质疏松症；脆性和去矿物化的骨头更多容易受到骨折的骨折，这是对老年人的主要问题。我们发现腺苷（几乎所有体液中都存在的物质）可以与受体结合对于破骨细胞的形成和功能至关重要，破骨细胞的细胞分解了骨骼。我们建议调查这些腺苷受体在调节骨重塑和腺苷及其接收器调节破骨细胞功能的机制。研究这里提出的与人类疾病直接相关，可能导致用于治疗和预防骨质疏松症的新疗法以及由此产生的易感性骨折在较早的情况下很常见。