Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum.
Oral supplementation of inorganic pyrophosphate in pseudoxanthoma elasticum.
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DOI：
10.1111/exd.14498
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发表时间：
2022-04
影响因子：
3.6
通讯作者：
Pomozi V
中科院分区：
文献类型：
--
作者：
Kozák E;Fülöp K;Tőkési N;Rao N;Li Q;Terry SF;Uitto J;Zhang X;Becker C;Váradi A;Pomozi V
弹性假黄瘤是一种罕见的遗传性多系统疾病，其特征是异位矿化影响皮肤、眼睛和心血管系统的弹性纤维。皮肤表现通常会导致PXE的早期诊断，但目前还没有特定的治疗方法来抵消症状的进展。PXE属于一组与焦磷代谢相关的孟德尔钙化疾病，还包括婴儿期全身性动脉钙化(GACI)和CD73缺乏所致的动脉钙化(ACDC)。ABCC6、ENPP1和NT5E的失活突变分别是这些疾病的遗传原因，所有这些突变都会导致循环中无机焦磷(PPI)浓度下降。虽然PPI是一种强烈的异位钙化抑制剂，但口服补充疗法最初没有考虑，因为它的生物利用度较低。然而，我们早期的工作表明，口服焦磷酸盐抑制了PXE和GACI动物模型中的异位钙化，口服Na4P2O7在人类中被吸收。在这里，我们报告了明胶包裹的Na2H2P2O7在健康志愿者和受PXE影响的人中具有相似的吸收特性。无钠K2H2P2O7形式在健康志愿者中导致类似的摄取，并与其钠相对应物一样有效地抑制Abcc6−/−小鼠的钙化。还鉴定了在小鼠中具有较高生物利用度的新型焦磷酸盐化合物。我们的结果为在PXE的临床试验中测试口服PPI提供了重要的一步，PXE或可能伴随异位钙化的任何情况，包括糖尿病、慢性肾脏疾病或老龄化。
Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibers in the skin, eyes, and the cardiovascular system. Skin findings often lead to early diagnosis of PXE, but currently no specific treatment exists to counteract the progression of symptoms. PXE belongs to a group of Mendelian calcification disorders linked to pyrophosphate metabolism, which also includes generalized arterial calcification of infancy (GACI), and arterial calcification due to CD73 deficiency (ACDC). Inactivating mutations in ABCC6, ENPP1 and NT5E are the genetic cause of these diseases, respectively, and all of them result in reduced inorganic pyrophosphate (PPi) concentration in the circulation. Although PPi is a strong inhibitor of ectopic calcification, oral supplementation therapy was initially not considered because of its low bioavailability. Our earlier work however demonstrated that orally administered pyrophosphate inhibits ectopic calcification in the animal models of PXE and GACI, and that orally given Na4P2O7 is absorbed in humans. Here we report that gelatin encapsulated Na2H2P2O7 has similar absorption properties in healthy volunteers and people affected by PXE. The sodium-free K2H2P2O7 form resulted in similar uptake in healthy volunteers, and inhibited calcification in Abcc6−/− mice as effectively as its sodium counterpart. Novel pyrophosphate compounds showing higher bioavailability in mice were also identified. Our results provide an important step toward testing oral PPi in clinical trials in PXE, or potentially any condition accompanied by ectopic calcification including diabetes, chronic kidney disease or ageing.
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影响因子：
11.1
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
通讯作者：
Váradi A
影响因子：
64.8
作者：
FLEISCH, H;RUSSEL, RGG;STRAUMANN, F
通讯作者：
STRAUMANN, F
影响因子：
3.9
作者：
Luo H;Li Q;Cao Y;Uitto J
通讯作者：
Uitto J
影响因子：
3.5
作者：
Gorgels, TGMF;Hu, XF;Bergen, AAB
通讯作者：
Bergen, AAB
DOI：
10.1161/atvbaha.114.304017
发表时间：
2014-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Jansen RS;Duijst S;Mahakena S;Sommer D;Szeri F;Váradi A;Plomp A;Bergen AA;Oude Elferink RP;Borst P;van de Wetering K
通讯作者：
van de Wetering K