ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions.
ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions.
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ABCC6，焦磷酸盐和异位钙化：治疗解决方案。
DOI：
10.3390/ijms22094555
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发表时间：
2021-04-27
影响因子：
5.6
通讯作者：
Le Saux O
中科院分区：
文献类型：
--
作者：
Shimada BK;Pomozi V;Zoll J;Kuo S;Martin L;Le Saux O
软组织的病理性（异位）矿化发生在衰老过程中，在一些常见的情况下，如糖尿病、高胆固醇血症、肾衰竭和某些遗传疾病中。弹性假性黄瘤（PXE）是一种影响皮肤、眼部和心血管组织的多器官疾病，是异位矿化疾病的典型。ABCC6功能障碍是PXE的主要原因，但也是婴儿期全身性动脉钙化（GACI）的一些病例。小鼠ABCC6缺乏是诱导性营养不良心脏钙化表型（DCC）的基础。这些钙化疾病是矿化疾病谱的一部分，也包括关节和动脉钙化（CALJA）。自从ABCC6被鉴定为“PXE基因”并建立了多种动物模型（小鼠、大鼠和斑马鱼）以来，我们对这些疾病的分子遗传学、临床表型和发病机制的理解取得了重大进展，这些疾病与更常见的异常钙化有相似之处。ABCC6促进ATP的细胞外排，ATP通过外核酶NPP1和CD73 （NT5E）迅速转化为无机焦磷酸（PPi）和腺苷。PPi是一种有效的内源性钙化抑制剂，而腺苷则通过抑制组织非特异性碱性磷酸酶（TNAP）的合成间接促进钙化抑制。目前，治疗方法仅能缓解PXE和GACI的症状；然而，广泛的研究已经产生了几种治疗PXE和GACI的新方法。本文旨在总结ABCC6在PXE和其他钙化疾病的异位钙化中的作用，并讨论针对该途径中各种蛋白（ABCC6、NPP1和TNAP）的治疗策略，以及通过补充各种化合物直接抑制钙化。
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.
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