Inorganic pyrophosphate generation and disposition in pathophysiology

Abstract

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