Inorganic Pyrophosphate Metabolism in Arthritis

描述(申请人提供)：二水焦磷酸钙(CPPD) 晶体沉着病是关节炎的一种常见形式，尤其是在 老年人。在80岁以上的人群中，患病率接近50%。CPPD晶体引起 痛风样关节炎的急性发作，但更重要的是与 衰弱的退行性关节炎。体外和体内数据强烈表明 这些晶体会导致或放大软骨退化。这项建议 重点介绍了无机焦磷酸盐(PPI)的来源，即阴离子成分 CPPD晶体。PPI代谢紊乱明显与慢性阻塞性肺疾病有关 晶体沉积。具体重点将放在潜在的机制上 在形成晶体的细胞外软骨基质中产生PPI。这个 胞外PPI(Eppi)产生的效应臂涉及胞外酶 核苷三磷酸焦磷水解酶(NTPPPH)，产生Eppi 来自细胞外的核苷三磷酸，如三磷酸腺苷。NTPPPH活性为 在关节软骨中高表达。胞外三磷酸腺苷的可用性 NTPPPH底物是Eppi产生的限速底物，最 这种三磷酸腺苷的细胞来源可能是软骨细胞。这些研究是 旨在确定调节Eppi形成的因素对 软骨细胞释放三磷酸腺苷。特别强调的是增长。 因子(转化生长因子-β和胰岛素样生长因子-I)，on 软骨细胞供体年龄，在转导途径(蛋白激酶C和 CAMP相关)，以及嘌呤受体(P1和P2)。前面提到的所有 软骨细胞对Eppi表达的影响。这项提议的第二个目标是 目的：探讨软骨细胞三磷酸腺苷外泄的机制。特定焦点 将在ATP结合盒蛋白上(人类ABC1和ABC1的类似物 软骨细胞表达的P-糖蛋白)，一种缝隙连接蛋白(连接蛋白 43)，ANK蛋白为可能的转运蛋白。这些研究的目的是 深入了解CPPD沉积疾病的发病机制，以便 可以产生治疗选项。

DESCRIPTION (provided by applicant): Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is a common form of arthritis, particularly in the elderly. Prevalence approaches 50 percent in those over 80. CPPD crystals cause acute attacks of gout-like arthritis, but more importantly are associated with debilitating degenerative arthritis. In vitro and in vivo data strongly suggest that these crystals cause or amplify cartilage degeneration. This proposal focuses on the source of inorganic pyrophosphate (PPi), the anion constituent of CPPD crystals. Disordered PPi metabolism is clearly implicated in CPPD crystal deposition. Specific emphasis will be placed on mechanisms underlying PPi generation in extracellular cartilage matrix where crystals form. The effector arm of extracellular PPi (ePPi) generation involves the ectoenzyme nucleoside triphosphate pyrophosphohydrolase (NTPPPH), which generates ePPi from extracellular nucleoside triphosphates such as ATP. NTPPPH activity is highly expressed in articular cartilage. The availability of extracellular ATP substrate for NTPPPH is rate-limiting for generation of ePPi and the most likely cellular source of that ATP is the chondrocyte. These studies are designed to determine the effects of factors that modulate ePPi formation upon the release of ATP from chondrocytes. Specific emphasis is placed on growth factors (transforming growth factor-beta and insulin-like growth factor-I), on chondrocyte donor age, on transduction pathways (protein kinase C and cAMP-related), and on purine receptors (P1and P2). All of the aforementioned influence ePPi elaboration by chondrocytes. The second goal of this proposal is to determine the mechanisms of ATP egress from chondrocytes. Specific focus will be on ATP binding cassette proteins (analogues of human ABC1 and p-glycoprotein expressed in chondrocytes), a gap junction protein (connexin 43), and ANK protein as possible transporters. The intent of these studies is to develop insights into the pathogenesis of CPPD deposition disease so that therapeutic options may be generated.