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Oral administration of pyrophosphate inhibits connective tissue calcification
#MMPMID28701330
Dedinszki D
; Szeri F
; Kozák E
; Pomozi V
; T?kési N
; Mezei TR
; Merczel K
; Letavernier E
; Tang E
; Le Saux O
; Arányi T
; van de Wetering K
; Váradi A
EMBO Mol Med
2017[Nov]; 9
(11
): 1463-1470
PMID28701330
show ga
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.
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