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 style="fixed-case">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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机译：分别由ABCC6和ENPP1中的失活突变引起的多种疾病，包括弹性假黄瘤（PXE）和婴儿的全身动脉钙化（GACI），由于血浆焦磷酸盐（PPi）降低而出现广泛的组织钙化。然而，一直认为口服PPi的生物利用度可以忽略不计。在这里，我们证明口服PPi后人体循环中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减弱了它们的异位钙化表型。值得注意的是，在怀孕期间为Enpp1突变的杂合子小鼠提供了0.3mM PPi的饮用水可强烈抑制其Enpp1 -/-后代的异位钙化。我们的工作表明，口服给药的PPi在人和小鼠中容易吸收，并在PXE和GACI的小鼠模型中抑制结缔组织钙化。 PPi被 style =“ fixed-case”> FDA 认为是安全的，因此，不仅对于作为这些目前难治的遗传性疾病的有效且极低成本的治疗方法具有巨大潜力，而且在其他涉及结缔组织钙化的疾病。
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