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的受体已经被靶向用于这样的治疗。 帕金森氏病和间接的风湿性关节炎等多种疾病。几 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骼病理学表现， 腺苷水平由于腺苷脱氨酶缺乏。我们之前观察到 腺苷A1受体调节多核巨噬细胞的刺激形成， 细胞培养的人外周血单核细胞，因此确定是否 腺苷A1受体也调节破骨细胞的形成，破骨细胞是一种相关的 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 腺苷受体阻断剂阻断卵巢切除小鼠的骨丢失。初步 研究进一步证明，在体外阻断腺苷A1受体， 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 进一步阐述我们的初步发现在第一个目标中，我们将研究 腺苷和腺苷A1受体与破骨细胞功能和骨 重塑并确认和扩展我们的初步研究第二个目标是 确定骨代谢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 核苷酸转化为腺苷（NPP-1、TNAP、CD39和CD73）。第三个目的是剖析 腺苷A1受体调节形成和 体外破骨细胞的功能，使用分子技术和 信号酶抑制剂。腺苷A1受体在细胞凋亡中起作用的证据 在调节破骨细胞的形成和功能中的关键作用， 用于治疗以破骨细胞介导的 骨吸收老龄化人口最紧迫的公共卫生问题之一是日益增加的 脆弱和脆性的骨骼，骨质疏松症;脆性和脱矿骨是更多 容易骨折，这是老年人的主要问题。我们发现 腺苷是一种存在于几乎所有体液中的物质，它可以与受体结合， 对破骨细胞（分解骨骼的细胞）的形成和功能至关重要。我们提出 研究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。研究 这里提出的是直接相关的人类疾病，并可能导致快速发展， 用于治疗和预防骨质疏松症以及由此产生的对骨质疏松症的易感性的新疗法 这在老年人中很常见。

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.¿