Inorganic Pyrophosphate Metabolism in Arthritis

关节炎中的无机焦磷酸代谢

• 批准号: 6876662
• 负责人: LAWRENCE M. RYAN
• 金额: $ 25.95万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876662
• 关键词: adenosine triphosphate; animal tissue; arthritis; articular cartilage; calcium phosphate; chondrocytes; enzyme activity; extracellular matrix; gap junctions; insulinlike growth factor; membrane channels; membrane transport proteins; metabolism disorder; northern blottings; pathologic process; phosphorus metabolism; polymerase chain reaction; protein kinase C; pseudogout; pyrophosphatase; pyrophosphates; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a common form of arthritis, particularly in the elderly. Prevalence approaches 50 percent in those over 80. CPPD crystals cause acute attacks of gout-like arthritis, but more importantly are associated with debilitating degenerative arthritis. In vitro and in vivo data strongly suggest that these crystals cause or amplify cartilage degeneration. This proposal focuses on the source of inorganic pyrophosphate (PPi), the anion constituent of CPPD crystals. Disordered PPi metabolism is clearly implicated in CPPD crystal deposition. Specific emphasis will be placed on mechanisms underlying PPi generation in extracellular cartilage matrix where crystals form. The effector arm of extracellular PPi (ePPi) generation involves the ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH), which generates ePPi from extracellular nucleoside triphosphates such as ATP. NTPPPH activity is highly expressed in articular cartilage. The availability of extracellular ATP substrate for NTPPPH is rate-limiting for generation of ePPi and the most likely cellular source of that ATP is the chondrocyte. These studies are designed to determine the effects of factors that modulate ePPi formation upon the release of ATP from chondrocytes. Specific emphasis is placed on growth factors (transforming growth factor-beta and insulin-like growth factor-I), on chondrocyte donor age, on transduction pathways (protein kinase C and cAMP-related), and on purine receptors (P1and P2). All of the aforementioned influence ePPi elaboration by chondrocytes. The second goal of this proposal is to determine the mechanisms of ATP egress from chondrocytes. Specific focus will be on ATP binding cassette proteins (analogues of human ABC1 and p-glycoprotein expressed in chondrocytes), a gap junction protein (connexin 43), and ANK protein as possible transporters. The intent of these studies is to develop insights into the pathogenesis of CPPD deposition disease so that therapeutic options may be generated.

性状（由申请人提供）：焦磷酸钙二水合物（CPPD） 晶体沉积病是关节炎的一种常见形式，特别是在 老人80岁以上人群的患病率接近50%。CPPD晶体导致 痛风样关节炎的急性发作，但更重要的是与 使人衰弱的退化性关节炎体外和体内数据强烈表明 这些晶体会导致或加剧软骨退化这项建议 着重于无机焦磷酸盐（PPi）的来源， CPPD晶体PPi代谢紊乱明显与CPPD有关 晶体沉积将特别强调基本机制， PPi在细胞外软骨基质中生成，其中晶体形成。的 胞外PPi（ePPi）产生的效应臂涉及胞外酶 核苷三磷酸焦磷酸水解酶（NTPPPH），产生ePPi 从细胞外核苷三磷酸如ATP。NTPPPH活性为 在关节软骨中高度表达。细胞外ATP的可用性 NTPPPH的底物对ePPi的产生是限速的， ATP的细胞来源可能是软骨细胞。这些研究 旨在确定调节ePPi形成的因素对 从软骨细胞中释放ATP。特别强调增长 因子（转化生长因子β和胰岛素样生长因子I）， 软骨细胞供体年龄，对转导途径（蛋白激酶C和 cAMP相关）和嘌呤受体（P1和P2）。所有上述 影响软骨细胞产生ePPi。该提案的第二个目标是 以确定ATP从软骨细胞中排出的机制。具体重点 将在ATP结合盒蛋白（人ABC 1和人ABC 2的类似物）上。 软骨细胞中表达的p-糖蛋白），间隙连接蛋白（连接蛋白 43），和ANK蛋白作为可能的转运蛋白。这些研究的目的是 深入了解CPPD沉积病的发病机制， 可以产生治疗选项。