INORGANIC PYROPHOSPHATE METABOLISM IN ARTHRITIS

二水合焦磷酸钙（CPPD）晶体沉积病是一种疾病

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.