Functional rescue of ABCC6 deficiency by 4-phenylbutyrate therapy reduces dystrophic calcification in Abcc6 ^−/− mice

Abstract

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.