Oral administration of pyrophosphate inhibits connective tissue calcification

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are genetic disorders characterized by extensive tissue calcification.
• These conditions result from inactivating mutations in ABCC6 and ENPP1, respectively, leading to reduced plasma pyrophosphate (PPi).
• The bioavailability of orally administered PPi was previously considered negligible.

Purpose of the Study:

• To investigate the bioavailability and therapeutic potential of orally administered pyrophosphate (PPi).
• To evaluate the efficacy of oral PPi in attenuating ectopic calcification in mouse models of PXE and GACI.

Main Methods:

• Administration of oral PPi to humans and assessment of circulating PPi concentrations.
• Treatment of PXE and GACI mouse models with PPi via drinking water.
• Assessment of ectopic calcification phenotype in treated mice and their offspring.

Main Results:

• Oral PPi administration led to increased PPi concentrations in human circulation.
• Oral PPi significantly attenuated ectopic calcification in mouse models of PXE and GACI.
• PPi in drinking water during pregnancy inhibited ectopic calcification in Enpp1-/- offspring.

Conclusions:

• Orally administered PPi is readily absorbed in humans and mice.
• Oral PPi effectively inhibits connective tissue calcification in relevant genetic disorder models.
• PPi presents a promising, safe, and low-cost therapeutic option for PXE, GACI, and other calcification disorders.