Purinergic Regulation of Bone Metabolism

嘌呤核苷腺苷调节心率等生理功能， 血管舒张和炎症以及腺苷受体已成为此类作用的目标 帕金森病和间接的类风湿关节炎等多种疾病。很少 研究探讨了腺苷及其受体在骨代谢中的作用 尽管儿童骨病理学明显升高，但 由于腺苷脱氨酶缺乏而导致腺苷水平升高。我们之前观察到 腺苷 A1 受体调节多核巨细胞的刺激形成 细胞通过培养的人外周血单核细胞，因此确定是否 腺苷 A1 受体还调节破骨细胞的形成，破骨细胞是一种相关的形式 多核巨细胞。我们惊讶地发现，在初步研究中， 腺苷受体的阻断或敲除可防止体外破骨细胞的形成。 此外，腺苷A1受体敲除小鼠体内骨形成增加 腺苷受体阻断可以阻止卵巢切除小鼠的骨质流失。初步 研究进一步表明，体外阻断腺苷 A1 受体会改变 破骨细胞生成所需的信号事件。我们提出四个目标来确认和 扩展我们的初步发现。在第一个目标中，我们将研究以下角色： 破骨细胞功能和骨中的腺苷和腺苷 A1 受体 重塑并确认和扩展我们的初步研究。第二个目标是 确定骨过程中腺苷生成的生化基础 使用缺乏转化细胞外腺嘌呤的酶的动物进行重塑 核苷酸至腺苷（NPP-1、TNAP、CD39 和 CD73）。第三个目的是剖析 腺苷A1受体调节形成的机制 结合分子技术和体外破骨细胞的功能 信号酶抑制剂。腺苷A1受体发挥作用的证明 在调节破骨细胞的形成和功能中的关键作用表明一种新的 用于治疗以破骨细胞介导为特征的疾病的治疗靶点 骨吸收。人口老龄化最紧迫的公共卫生问题之一是日益增长的人口老龄化 骨骼脆弱、骨质疏松；脆性和脱矿质的骨头更严重 容易骨折，这是老年人的一大问题。我们发现 腺苷是一种几乎存在于所有体液中的物质，可以与受体结合， 对于破骨细胞（分解骨骼的细胞）的形成和功能至关重要。我们建议 研究这些腺苷受体在调节骨重塑中的作用以及 腺苷及其受体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，并可能导致快速发展 治疗和预防骨质疏松症及其易感性的新疗法 骨折在老年人中很常见。¿

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.¿