INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

关节炎中的无机焦磷酸盐代谢

• 批准号: 2517439
• 负责人: LAWRENCE M. RYAN
• 金额: $ 20.09万
• 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 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517439
• 关键词: animal tissue; arthritis; articular cartilage; calcium phosphate; chondrocytes; enzyme mechanism; extracellular matrix; metabolism disorder; pathologic process; phosphorus metabolism; pseudogout; pyrophosphatase; pyrophosphates; tissue /cell culture

DESCRIPTION: (Adapted from the applicant's abstract) - This is a renewal request for 5 years of support to study CPPD crystal deposition disease. This is a common form of arthritis, particularly in the elderly. Prevalence approaches 50% in those over 80. This disease is associated with acute attacks of gout-like arthritis termed pseudogout, but more importantly, with debilitating degenerative arthritis. These studies are aimed at determining the mechanism(s) of CPPD crystal formation in cartilage so that logical therapeutic and prophylactic interventions may be formulated. This proposal focuses on the role of inorganic pyrophosphate (PPi), the anionic constituent of CPPD crystals, in disease pathogenesis. Disordered PPi metabolism has been strongly implicated in CPPD crystal deposition. Specifically emphasized will be experiments to determine the mechanism controlling PPi generation in the extracellular cartilage matrix (where crystals form) by the ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH), which generates extracellular PPi from nucleoside triphosphate substrates such as ATP. Elevated NTPPPH activity has been clinically linked to CPPD deposition disease in studies of joint fluid and diseased cartilage. And NTPPPH is remarkably enriched in articular cartilage vesicles (ACV), matrix vesicles which mineralize to form CPPD in the presence of ATP substrate. They will test the hypotheses that: chondrocytes are the source of extracellular ATP substrate for NTPPPH; that ACV enriched in NTPPPH are biologically regulated; that ACV formation of CPPD crystals is pharmacologically inhibitable; that ACV formation of CPPD crystals is modified by cartilage matrix components; and that a specific molecular form of NTPPPH is necessary for CPPD formation in cartilage and in isolated ACV. New insights into these processes may suggest therapeutic approaches.

描述：（改编自申请人的摘要）-这是一个更新 请求5年的支持，研究CPPD晶体沉积病。 这是关节炎的一种常见形式，尤其是在老年人中。 患病率 在80岁以上的人中接近50%。 这种疾病与急性 痛风样关节炎称为假痛风，但更重要的是， 使人衰弱的退化性关节炎 这些研究旨在确定 CPPD晶体在软骨中形成的机制， 可以制定治疗和预防干预措施。 该建议侧重于无机焦磷酸盐（PPi）的作用， CPPD晶体的阴离子成分，在疾病的发病机制。 无序 PPi代谢与CPPD晶体沉积密切相关。 特别强调的是实验，以确定机制 控制细胞外软骨基质中PPi的产生（其中 晶体形式）由胞外酶核苷三磷酸 焦磷酸水解酶（NTPPPH），其从细胞外产生PPi， 核苷三磷酸底物如ATP。 NTPPPH活性升高 在关节炎研究中， 液体和病变的软骨。 而且NTPPPH明显富含 关节软骨囊泡（ACV），矿化形成的基质囊泡 在ATP底物存在下的CPPD。 他们将检验以下假设： 软骨细胞是NTPPPH的细胞外ATP底物的来源; 富含NTPPPH的ACV是生物调节的; CPPD晶体是可分解的; CPPD的ACV形成 晶体被软骨基质成分修饰;并且特定的 NTPPPH的分子形式对于软骨中CPPD的形成是必需的， 隔离ACV。 对这些过程的新见解可能表明治疗 接近。