Oral administration of pyrophosphate inhibits connective tissue calcification.
Dóra Dedinszki, Flóra Szeri, Eszter Kozák, Viola Pomozi, Natália Tőkési, Tamás Róbert Mezei, Kinga Merczel, Emmanuel Letavernier, Ellie Tang, Olivier Le Saux, Tamás Arányi, Koen van de Wetering, András Váradi
Author Information
Dóra Dedinszki: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Flóra Szeri: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Eszter Kozák: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Viola Pomozi: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Natália Tőkési: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Tamás Róbert Mezei: Department of Mathematics and its Applications Central European University, Budapest, Hungary.
Kinga Merczel: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Emmanuel Letavernier: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1155, Paris, France.
Ellie Tang: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1155, Paris, France.
Olivier Le Saux: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
Tamás Arányi: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
Koen van de Wetering: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
András Váradi: Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary varadi.andras@ttk.mta.hu. ORCID
Various disorders including pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI), which are caused by inactivating mutations in and , 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 during pregnancy robustly inhibited ectopic calcification in their 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.
