Abstract
Pseudoxanthoma elasticum (PXE) is a rare inherited disorder marked by abnormal calcium phosphate deposition in soft connective tissues, particularly the skin, arteries, and eyes. It is caused by inactivating mutations in the ABCC6 gene, which encodes a hepatic efflux transporter. Loss of ABCC6 function leads to reduced plasma levels of pyrophosphate (PPi), a key inhibitor of calcification, thereby promoting ectopic mineralization. Oral PPi therapy has emerged as a potential treatment, but its effectiveness is uncertain. Most ingested PPi is hydrolyzed in the gut to inorganic phosphate, which may worsen calcification. Moreover, its impact on mineralized tissues remains largely unexplored. Abcc6-/- mice closely mimic human PXE and are widely used in preclinical studies. Although patients are most concerned about ocular complications, eye calcification is rarely assessed in translational studies using Abcc6-/- mice. Using micro-CT, we found that ectopic calcification at the ciliary margin is a reliable marker of ocular disease progression in these mice. Administering PPi in drinking water at concentrations up to 90 mM did not increase calcification in skin or eyes. However, only very high doses effectively prevented ectopic calcification-doses that would equate to an impractical 2.5 g/kg/d of disodium PPi in humans. These high doses also led to PPi accumulation in bone and negatively affected bone structure and strength. In summary, only supraphysiological doses of orally administered PPi inhibited ectopic calcification in Abcc6-/- mice, but these doses are not feasible for human use and may compromise bone function. These data are especially important considering the currently ongoing clinical trial evaluating the safety and efficacy of oral PPi administration as a treatment for PXE.