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).

Osteoarthritis: Is it a disease of cartilage or of bone?

“…Absence of, or nonfunctioning, PC-1 has been associated with hyperossification, including ossification of paraspinal ligaments in mice, similar to that seen in DISH and ankylosing spondylitis (30). Similar findings arise with a mutation in the Ank gene.…”

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

“…Possible sources of synovial ePPi include the subchondral bone, the synovium, the meniscus (102), and the articular cartilage. In organ culture, the synovium does not elaborate ePPi (103), and subchondral bone absorbs ePPi (104), leaving meniscal cells and articular chondrocytes as the likely sources of ePPi (13,105). Pyrophosphate is either released from the cells or formed from eATP metabolism.…”

“…The tissue distribution of the PPi transporter has not been addressed in adult, aged, OA, or calcified articular cartilage. The clinical and genetic basis for ANK involvement in chondrocalcinosis has been reviewed elsewhere (4,13,35).…”

“…These vesicles have the unique ability to elaborate BCP and CPPD crystals from extracellular inorganic phosphate (ePi) and extracellular inorganic pyrophosphate (ePPi), respectively. The balance between ePi and ePPi must be tightly regulated, since ePPi prevents BCP crystal formation (10,11), while excess ePPi leads to CPPD crystal deposition (12,13).…”

“…The ank-null mouse phenotype resembles that of the ttw/ttw mouse generated by a truncation in the NPP1 gene (14). Thus, NPP1 and ANK may both contribute to ePPi accumulation in the ECM (13,35,36). Because PPi is also generated from extracellular nucleotide metabolism, it was suggested that ANK might transport ATP rather than, or in addition to, PPi (37).…”