INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

这些研究的长期目标是更好地阐明 二水焦磷酸钙(CPPD)晶体的发病机制 沉积病，一种常见的关节炎形式，所以合乎逻辑 可以制定治疗和/或预防的方法。 无机焦磷酸盐(PPI)代谢紊乱 与CPPD晶体的形成密切相关 在体内形成。最近的报告通过以下方式支持这一假设 培养细胞内PPI升高 有家族性CPPD沉积的单亲； 核苷三磷酸焦磷水解酶(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 存在于两种疾病患者皮肤来源的成纤维细胞中 散发性和家族性CPPD沉积病；NTPPPH活性 在关节液和培养细胞表面升高 慢性阻塞性肺疾病患者软骨细胞上的NTPPPH沉积 胞外能产生PPI的胞外酶 软骨中形成CPPD晶体的地方。 这项建议将具体旨在确定：(1)如果提高 细胞内PPI是有效的疾病标记物；(2)代谢 细胞内PPI的来源；(3)Etro-NTPPPH升高是否 也是疾病的“标志物”；(4)细胞外底物是否 可在软骨中与ecto-NTPPPH相互作用，从而 产生胞外PPI；(5)哪些因素调节NTPPPH 活动；(6)哪些生理生化因素会影响PPI 通过软骨进行精加工。关于软骨细胞的认识 我们收集到的胞外酶将被用来设计一种体内的 CPPD沉积的软骨器官培养模型 促进治疗干预和治疗干预的研究 软骨中晶体的生物化学效应。

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.