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.

Soft tissue calcification is associated with aging, common conditions such as diabetes or hypercholesterolemia and with certain genetic disorders. ABCC6 is an efflux transporter primarily expressed in liver facilitating the release of ATP from hepatocytes. Within the liver vasculature, ATP is converted into pyrophosphate (PPi), a major inhibitor of ectopic calcification. ABCC6 mutations thus lead to reduced plasma PPi levels resulting in the calcification disorder pseudoxanthoma elasticum (PXE) and some cases of generalized arterial calcification of infancy (GACI). Most mutations in ABCC6 are missense and many retain/preserve transport activity but are retained intracellularly. We have previously shown that the chemical chaperone 4-phenylbutyrate (4-PBA) promotes the maturation of ABCC6 mutants to the plasma membrane. In a humanized mouse model of PXE, we investigated whether 4-PBA treatments could rescue the calcification inhibition potential of selected ABCC6 mutants. We used the dystrophic cardiac calcification (DCC) phenotype of Abcc6−/− mice as an indicator of ABCC6 function to quantify the effect of 4-PBA on human ABCC6 mutants transiently expressed in the liver. We showed that 4-PBA administrations restored the physiological function of ABCC6 mutants resulting in enhanced calcification inhibition. This study identifies 4-PBA treatments as a promising strategy for allele-specific therapy of ABCC6-associated calcification disorders.