INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

关节炎中的无机焦磷酸盐代谢

• 批准号: 3158698
• 负责人: LAWRENCE M. RYAN
• 金额: $ 9.96万
• 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 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3158698
• 关键词: arthritis; calcium phosphate; cartilage; chondrocytes; crystallization; enzyme mechanism; human tissue; organ culture; pyrophosphates; tissue /cell culture

The long-term objective of these studies is to better elucidate the pathogenesis of calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, a common form of arthritis, so that logical approaches to treatment and/or prophylaxis may be formulated. Disordered inorganic pyrophosphate (PPi) metabolism has been strongly implicated as a factor in contributing to CPPD crystal formation in vivo. Recent reports support this hypothesis by demonstrating elevated intracellular PPi in cultured cells of a single kindred with familial CPPD deposition; and elevated nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity, which generates PPi, in CPPD-containing cartilage. Subsequent and preliminary studies suggest that: elevated intracellular PPi is present in skin-derived fibroblasts from patients with both sporadic and familial CPPD deposition disease; NTPPPH activity is elevated in joint fluids and on the surface of cultured cells for patients with CPPD deposition; NTPPPH on chondrocytes in an ectoenzyme capable of generating PPi at the extracellular site where CPPD crystals form in cartilage. This proposal will specifically aim at determining: (1) if elevated intracellular PPi is a valid disease "marker"; (2) the metabolic source of intracellular PPi; (3) whether elevated ecto-NTPPPH is also a disease "marker"; (4) whether extracellular substrate is available in cartilage to interact with ecto-NTPPPH, thereby generating extracellular PPi; (5) which factors modulate NTPPPH activity; (6) what physical and biochemical factors affect ppi elaboration by cartilage. The knowledge of chondrocyte ectoenzymes which we glean will be used to devise an in vivo cartilage organ culture model of CPPD deposition which would facilitate studies of therapeutic interventions and of the biochemical effects of crystals in cartilage.

这些研究的长期目标是更好地阐明 二水焦磷酸钙晶体形成机理 沉积病，关节炎的一种常见形式，所以，逻辑 可以制定治疗和/或预防的方法。 无机焦磷酸盐（PPi）代谢紊乱， 强烈暗示是促成CPPD结晶的因素 在体内形成。 最近的报告支持这一假设， 证明在培养的细胞中， 具有家族性CPPD沉积的单一亲属;以及 核苷三磷酸焦磷酸水解酶（NTPPPH）活性， 在含有CPPD的软骨中产生PPi。 后续 初步研究表明：细胞内PPi升高是 存在于皮肤来源的成纤维细胞中， 散发性和家族性CPPD沉积病 在关节液和培养细胞的表面， CPPD沉积的患者; NTPPPH对软骨细胞的作用， 能够在胞外位点产生PPi的胞外酶 CPPD晶体在软骨中形成 本建议的具体目的是确定：（1）如果提高 细胞内PPi是有效的疾病“标志物”;（2）代谢性PPi是一种有效的疾病“标志物”。 细胞内PPi的来源;（3）升高的外-NTPPPH是否是 也是一种疾病“标志物”;（4）细胞外底物是否 可在软骨中与外-NTPPPH相互作用， 产生胞外PPi;（5）哪些因子调节NTPPPH 活动;（6）哪些物理和生化因素影响运动 由软骨加工。 软骨细胞的知识 我们收集的胞外酶将用于设计一种体内 CPPD沉积的软骨器官培养模型， 促进治疗干预措施和 软骨中晶体的生化作用。