INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

焦磷酸钙二水合物（CPPD）晶体沉积病是一种 常见的关节炎，尤其是老年人。 患病率 在80岁以上的人中接近90%。 这种疾病与急性 痛风样关节炎的发作称为假痛风，但更重要的是， 患有退化性关节炎 这些研究旨在 确定软骨中CPPD晶体形成的机制， 可以制定合理的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 疾病 特别强调的是实验，以确定 PPi（一种正常的细胞内分子）到达细胞的机制 CPPD晶体形成的细胞外空间;并设计体外 CPPD沉积模型。 待检验的假设包括：1. PPi是否 从细胞中排出是细胞的一般性渗透的一部分，或者是 由阴离子转运蛋白介导（输出假说）; 2. PPi是否 软骨细胞与基质大分子共分泌 （共分泌假说）;或3. PPi是否在细胞外产生， 胞外酶-核苷三磷酸焦磷酸水解酶（胞外酶 假设）。 体外模型将基于我们的背景知识 的NTPPPH，其在晶体形成的位点产生PPi， 软骨 将使用软骨细胞和软骨外植体培养物 广泛用于PPi研究;软骨外植体和囊泡来源 将用于CPPD晶体 形成模式 定义潜在的代谢异常 疾病和更好地理解晶体发生提供了两个层次的 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.