INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

摘要二水焦磷酸钙(CPPD)晶体沉积症是一种 关节炎的常见形式，尤其是在老年人中。流行率 在80岁以上的人群中接近90%。这种疾病与急性 痛风性关节炎的发作被称为假性痛风，但更重要的是， 患有衰弱的退行性关节炎。这些研究的目的是 确定CPPD在软骨中的晶体形成机制 可以制定合理的治疗和预防干预措施。 这项建议的重点是无机焦磷酸盐(PPI)的作用， CPPD晶体中的阴离子成分，在疾病发病机制中。无序的 PPI代谢与CPPD晶体沉积密切相关 疾病。特别强调的是用实验来确定 (S)PPI，一种正常的细胞内分子，通过其到达 形成CPPD晶体的细胞外空间；并设计一种体外 CPPD沉积模型。有待检验的假设包括：1.购买力平价是否 细胞出口是细胞普遍恒定的一部分，或者是 由阴离子转运体介导(输出假说)；2.PPI是否 软骨细胞与基质定向大分子共分泌 (共分泌假说)；或3.PPI是否由细胞外产生 胞外酶-核苷三磷酸焦磷水解酶(胞外酶) 假设)。体外模型将基于我们的背景知识 ，它在晶体形成的位置产生PPI 软骨。将使用软骨细胞和软骨移植培养 广泛用于PPI研究；以及软骨外植体和提取的囊泡 来自关节软骨的消化液将用于CPPD晶体 队形模型。定义了在此基础上的代谢异常 疾病和对晶体发生的更好理解提供了两个层面的 潜在的治疗干预。

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a common form of arthritis, particularly in the elderly. Prevalence approaches 90% 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 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 component of CPPD crystals, in disease pathogenesis. Disordered PPi metabolism has been strongly implicated in CPPD crystal deposition disease. Specifically emphasized will be experiments to determine the mechanism(s) by which PPi, a normally intracellular molecule, reaches the extracellular space where CPPD crystals form; and to devise an in vitro model of CPPD deposition. Hypotheses to be tested include: 1. whether PPi egress from cells is part of a generalized permabilization of cells or is mediated by an anion transporter (export hypothesis); 2. whether PPi is cosecreted from chondrocytes with matrix-destined macromolecules (cosecretion hypothesis); or 3. whether PPi is generated extracellularly by the ectoenzyme-nucleoside triphosphate pyrophosphohydrolase (ectoenzyme hypothesis). The in vitro model will be based on our background knowledge of NTPPPH, which generates PPi at the site of crystal formation in cartilage. Chondrocyte and cartilage explant cultures will be used extensively for PPi studies; and cartilage explants and vesicles derived from articular cartilage digests will be used for the CPPD crystal formation model. Defining the metabolic abnormality(ies) underlying this disease and better understanding crystallogenesis offers two levels of potential therapeutic intervention.