Open AccessOral administration of pyrophosphate inhibits connective tissue calcification
Author(s) -
Dedinszki Dóra,
Szeri Flóra,
Kozák Eszter,
Pomozi Viola,
Tőkési Natália,
Mezei Tamás Róbert,
Merczel Kinga,
Letavernier Emmanuel,
Tang Ellie,
Le Saux Olivier,
Arányi Tamás,
Wetering Koen,
Váradi András
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201707532
Subject(s) - calcification , connective tissue , pyrophosphate , medicine , chemistry , pathology , pharmacology , biochemistry , enzyme
Various disorders including pseudoxanthoma elasticum ( PXE ) and generalized arterial calcification of infancy ( GACI ), which are caused by inactivating mutations in ABCC 6 and ENPP 1 , respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate ( PP i). However, it has always been assumed that the bioavailability of orally administered PP i is negligible. Here, we demonstrate increased PP i concentration in the circulation of humans after oral PP i administration. Furthermore, in mouse models of PXE and GACI , oral PP i provided via drinking water attenuated their ectopic calcification phenotype. Noticeably, provision of drinking water with 0.3 mM PP i to mice heterozygous for inactivating mutations in Enpp1 during pregnancy robustly inhibited ectopic calcification in their Enpp1 −/− offspring. Our work shows that orally administered PP i is readily absorbed in humans and mice and inhibits connective tissue calcification in mouse models of PXE and GACI . PP i, which is recognized as safe by the FDA , therefore not only has great potential as an effective and extremely low‐cost treatment for these currently intractable genetic disorders, but also in other conditions involving connective tissue calcification.