Inorganic pyrophosphate generation and disposition in pathophysiology

Inorganic pyrophosphate (PP_i)regulates certain intracellular functions and extracellular crystaldeposition. PP_i is produced, degraded, and transported byspecialized mechanisms. Moreover, dysregulated cellular PP_iproduction, degradation, and transport all have been associated withdisease, and PP_i appears to directly mediate specificdisease manifestations. In addition, natural and synthetic analogs ofPP_i are in use or currently under evaluation asprophylactic agents or therapies for disease. This review summarizes recent developments in the understanding of how PP_i is madeand disposed of by cells and assesses the body of evidence forpotentially significant physiological functions of intracellularPP_i in higher organisms. Major topics addressed are recentlines of molecular evidence that directly link decreased and increasedextracellular PP_i levels with diseases in which connectivetissue matrix calcification is disordered. To illustrate in depth theeffects of disordered PP_i metabolism, this review weighsthe roles in matrix calcification of the transmembrane protein ANK,which regulates intracellular to extracellular movement ofPP_i, and the PP_i-generating phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1).