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, T. Arányi, Koen van de Wetering, A. Váradi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1463-1470
Number of pages8
JournalEMBO Molecular Medicine
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Pseudoxanthoma Elasticum
Connective Tissue
Oral Administration
Drinking Water
Mutation
Inborn Genetic Diseases
Health Care Costs
Biological Availability
Phenotype
Pregnancy
diphosphoric acid
Arterial calcification of infancy

Keywords

  • generalized arterial calcification of infancy
  • oral pyrophosphate treatment
  • pseudoxanthoma elasticum
  • soft tissue calcification

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Dedinszki, D., Szeri, F., Kozák, E., Pomozi, V., Tőkési, N., Mezei, T. R., ... Váradi, A. (2017). Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Molecular Medicine, 9(11), 1463-1470. https://doi.org/10.15252/emmm.201707532

Oral administration of pyrophosphate inhibits connective tissue calcification. / Dedinszki, Dóra; Szeri, Flóra; Kozák, Eszter; Pomozi, Viola; Tőkési, Natália; Mezei, Tamás Róbert; Merczel, Kinga; Letavernier, Emmanuel; Tang, Ellie; Le Saux, Olivier; Arányi, T.; van de Wetering, Koen; Váradi, A.

In: EMBO Molecular Medicine, Vol. 9, No. 11, 01.11.2017, p. 1463-1470.

Research output: Contribution to journalArticle

Dedinszki, D, Szeri, F, Kozák, E, Pomozi, V, Tőkési, N, Mezei, TR, Merczel, K, Letavernier, E, Tang, E, Le Saux, O, Arányi, T, van de Wetering, K & Váradi, A 2017, 'Oral administration of pyrophosphate inhibits connective tissue calcification', EMBO Molecular Medicine, vol. 9, no. 11, pp. 1463-1470. https://doi.org/10.15252/emmm.201707532
Dedinszki D, Szeri F, Kozák E, Pomozi V, Tőkési N, Mezei TR et al. Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Molecular Medicine. 2017 Nov 1;9(11):1463-1470. https://doi.org/10.15252/emmm.201707532
Dedinszki, Dóra ; Szeri, Flóra ; Kozák, Eszter ; Pomozi, Viola ; Tőkési, Natália ; Mezei, Tamás Róbert ; Merczel, Kinga ; Letavernier, Emmanuel ; Tang, Ellie ; Le Saux, Olivier ; Arányi, T. ; van de Wetering, Koen ; Váradi, A. / Oral administration of pyrophosphate inhibits connective tissue calcification. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 11. pp. 1463-1470.
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