Oral administration of pyrophosphate inhibits connective tissue calcification

Abstract

Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in ABCC6 and ENPP1, respectively, present with extensive tissue calcification due to reduced plasma pyrophosphate (PPi). However, it has always been assumed that the bioavailability of orally administered PPi is negligible. Here, we demonstrate increased PPi concentration in the circulation of humans after oral PPi administration. Furthermore, in mouse models of PXE and GACI, oral PPi provided via drinking water attenuated their ectopic calcification phenotype. Noticeably, provision of drinking water with 0.3 mM PPi to mice heterozygous for inactivating mutations in Enpp1 during pregnancy robustly inhibited ectopic calcification in their Enpp1 −/− offspring. Our work shows that orally administered PPi is readily absorbed in humans and mice and inhibits connective tissue calcification in mouse models of PXE and GACI. PPi, 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.

Microvasculopathy And Soft Tissue Calcification In Mice Are Governed by Fetuin-A, Pyrophosphate And Magnesium

“…In addition to PXE and GACI, Hutchinson-Gilford progeria syndrome (HGPS), was linked to reduced PPi levels associated with the development of extracellular matrix calcification [13]. Although mouse models for HGPS, GACI and PXE show promising results when treated with PPi, human studies remain to be conducted [65].…”

Inhibition of Tissue-Nonspecific Alkaline Phosphatase Attenuates Ectopic Mineralization in the Abcc6 Mouse Model of PXE but Not in the Enpp1 Mutant Mouse Models of GACI

“…After centrifugation, plasma was depleted of platelets by filtration through a Centrisart I 300-kDa mass cutoff filter (Sartorius, New York, NY) and stored at e80 C until further processing. PPi in plasma was measured by an enzymatic reaction using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5 0 -phosphosulfate (Sigma-Aldrich), a methodology adopted worldwide as described previously (Bauer et al, 2018;Dedinszki et al, 2017;Jansen et al, 2014;Li et al, 2017;Pomozi et al, 2017).…”

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

“…A different genetic background of their Ank ank/ank mice might underlie this more dramatic effect. Food composition, specifically varying PPi content 31 , might also have contributed to the differences found in BMD between the two studies.…”

“…ANK can therefore be expected to be responsible for part of the remaining 30-40% of the PPi present in plasma that is independent of ABCC6 activity. The relatively small contribution of ANK together with the large variability in plasma PPi concentrations 10,11,31 prevents determination of the contribution of ANK to plasma PPi in Ank ank/ank mice. Ank ank/ank ; Abcc6 −/− compound mutant mice ( Ank ank ; Abcc6 tm1Jfk ) provide the optimal experimental model system to determine the contribution of ANKH/ANK to plasma PPi.…”