INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

描述：(改编自申请人的摘要)-这是一份续签 申请5年支持，研究慢性阻塞性肺病晶体沉积症。 这是一种常见的关节炎，尤其是在老年人中。流行率 在80岁以上的人群中接近50%。这种疾病与急性 痛风样关节炎的发作被称为假性痛风，但更重要的是， 衰弱的退行性关节炎。这些研究的目的是确定 CPPD在软骨中晶体形成的机制(S)使逻辑 可制定治疗性和预防性干预措施。 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。 特别强调的是用实验来确定这种机制。 控制细胞外软骨基质中PPI的产生(其中 晶体)由胞外酶核苷三磷酸形成 焦磷水解酶(NTPPPH)，从细胞外产生PPI 三磷酸核苷底物，如三磷酸腺苷。NTPPPH活性升高 已经在临床上与关节研究中的CPPD沉积疾病有关 软骨积液和病变。和NTPPPH显著富含 关节软骨小泡(ACV)，基质小泡，矿化形成 CPPD在有ATP底物存在的情况下。他们将检验以下假设： 软骨细胞是NTPPPH细胞外ATP底物的来源； 富含NTPPPH的ACV受到生物调节；ACV的形成 CPPD晶体在药物上是可抑制的；CPPD的ACV形成 晶体是由软骨基质成分修饰的；并且特定的 NTPPPH的分子形式对软骨和软骨中CPPD的形成是必需的 分离的ACV。对这些过程的新见解可能会提示治疗 接近了。

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.