Inorganic pyrophosphate generation and disposition in pathophysiology

Abstract

Inorganic pyrophosphate (PPi) regulates certain intracellular functions and extracellular crystal deposition. PPiis produced, degraded, and transported by specialized mechanisms. Moreover, dysregulated cellular PPiproduction, degradation, and transport all have been associated with disease, and PPiappears to directly mediate specific disease manifestations. In addition, natural and synthetic analogs of PPiare in use or currently under evaluation as prophylactic agents or therapies for disease. This review summarizes recent developments in the understanding of how PPiis made and disposed of by cells and assesses the body of evidence for potentially significant physiological functions of intracellular PPiin higher organisms. Major topics addressed are recent lines of molecular evidence that directly link decreased and increased extracellular PPilevels with diseases in which connective tissue matrix calcification is disordered. To illustrate in depth the effects of disordered PPimetabolism, this review weighs the roles in matrix calcification of the transmembrane protein ANK, which regulates intracellular to extracellular movement of PPi, and the PPi-generating phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1).