Purinergic Regulation of Bone Metabolism

嘌呤核苷腺苷调节心率等生理功能， 血管扩张和炎症以及腺苷受体已成为此类疾病的靶点 各种疾病，如帕金森氏症，以及间接的类风湿性关节炎。一些 研究表明腺苷及其受体在骨代谢中的作用。 尽管在儿童中有明显的骨性病理表现，但 腺苷脱氨酶缺乏所致的腺苷水平。我们之前观察到 腺苷A1受体调控多核巨细胞的刺激形成 通过培养人外周血单核细胞，从而确定 腺苷A1受体也调节破骨细胞的形成，破骨细胞是一种与 多核巨细胞。我们惊讶地发现，在初步研究中， 阻断或敲除腺苷受体可在体外阻止破骨细胞的形成。 此外，腺苷A1受体基因敲除小鼠在体内增加了骨形成 腺苷受体阻滞剂可以阻止去卵巢小鼠的骨质丢失。初步 研究进一步证明，在体外阻断腺苷A1受体会改变 破骨细胞发生所需的信号事件。我们提出四个目标，以确认和 对我们的初步调查结果进行扩展。在第一个目标中，我们将考察 腺苷和腺苷A1受体与破骨细胞功能和骨 并在我们的初步研究上进行了确认和扩展。第二个目标是 确定骨骼过程中腺苷生成的生化基础 利用细胞外腺嘌呤转化酶缺陷的动物进行重构 核苷酸到腺苷(NPP-1、TNAP、CD39和CD73)。第三个目标是剖析 腺苷A1受体调节细胞的形成和 联合应用分子生物学技术研究破骨细胞的体外功能 信号酶的抑制剂。腺苷A1受体发挥作用的证据 在调节破骨细胞的形成和功能中的关键作用提示了一种新的 破骨细胞介导的疾病的治疗靶点 骨吸收。老龄化人口面临的最紧迫的公共卫生问题之一是日益增长的 骨骼的脆性和脆性，骨质疏松症；脆性和去矿化骨要多得多 容易骨折，这是老年人的一个主要问题。我们发现， 腺苷是一种存在于几乎所有体液中的物质，它可以与一种受体结合，这种受体 对破骨细胞的形成和功能至关重要，破骨细胞是分解骨骼的细胞。我们建议 目的：探讨这些腺苷受体在调节骨重建中的作用。 腺苷及其受体调节破骨细胞功能的机制。这些研究 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引起的骨质疏松症易感性的新疗法 在老年人中很常见的骨折。

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.¿