Oral administration of pyrophosphate inhibits connective tissue calcification.
Oral administration of pyrophosphate inhibits connective tissue calcification.
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DOI：
10.15252/emmm.201707532
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发表时间：
2017-11
影响因子：
11.1
通讯作者：
Váradi A
中科院分区：
文献类型：
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作者：
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
各种疾病包括弹性假黄瘤(PXE)和婴儿期全身性动脉钙化(GACI)，分别由ABCC6和ENPP1的失活突变引起，由于血浆焦磷酸(PPI)减少而出现广泛的组织钙化。然而，人们一直认为口服PPI的生物利用度可以忽略不计。在这里，我们证明了口服PPI后，人体循环中的PPI浓度增加。此外，在PXE和GACI的小鼠模型中，通过饮用水提供的口服PPI减轻了它们的异位钙化表型。值得注意的是，在怀孕期间向Enpp1基因突变失活杂合子小鼠提供0.3mMppi的饮用水，有力地抑制了它们Enpp1−/−后代的异位钙化。我们的工作表明，口服PPI很容易在人和小鼠体内吸收，并抑制PXE和GACI小鼠模型中结缔组织的钙化。因此，PPI被FDA认为是安全的，不仅在这些目前难以治愈的遗传性疾病中具有巨大的潜力和极低的成本，而且在涉及结缔组织钙化的其他情况下也具有巨大的潜力。
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.