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EMBO Mol Med. 2017 Nov;9(11):1463-1470. doi: 10.15252/emmm.201707532.

Oral administration of pyrophosphate inhibits connective tissue calcification.

Author information

1
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary.
2
Department of Immunology, ELTE, Budapest, Hungary.
3
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
4
Department of Mathematics and its Applications Central European University, Budapest, Hungary.
5
Alfréd Rényi Institute of Mathematics, Hungarian Academy of Sciences, Budapest, Hungary.
6
Sorbonne Universités, UPMC Univ Paris 06, UMR S 1155, Paris, France.
7
INSERM, UMR S 1155, Paris, France.
8
Physiology Unit, AP-HP, Hôpital Tenon, Paris, France.
9
MITOVASC, CNRS UMR 6015, Inserm U1083, University of Angers, Angers, France.
10
Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
11
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, Hungary varadi.andras@ttk.mta.hu.

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.

KEYWORDS:

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

PMID:
28701330
PMCID:
PMC5666306
DOI:
10.15252/emmm.201707532
[Indexed for MEDLINE]
Free PMC Article

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