Shimada Briana K, Pomozi Viola, Zoll Janna, Kuo Sheree, Martin Ludovic, Le Saux Olivier
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96817, USA.
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
Int J Mol Sci. 2021 Apr 27;22(9):4555. doi: 10.3390/ijms22094555.
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.
软组织的病理性（异位）矿化在衰老过程中、在糖尿病、高胆固醇血症和肾衰竭等几种常见病症以及某些遗传性疾病中都会发生。弹性假黄瘤（PXE）是一种影响皮肤、眼部和心血管组织的多器官疾病，是异位矿化疾病的一个模型。ABCC6功能障碍是PXE的主要病因，也是婴儿期全身性动脉钙化（GACI）的部分病例的病因。小鼠中的ABCC6缺陷是诱导性营养不良性心脏钙化表型（DCC）的基础。这些钙化疾病是矿化障碍谱系的一部分，该谱系还包括关节和动脉钙化（CALJA）。自从ABCC6被鉴定为“PXE基因”以及几种动物模型（小鼠、大鼠和斑马鱼）的开发以来，我们在对这些疾病的分子遗传学、临床表型和发病机制的理解方面取得了重大进展，这些疾病与钙化异常的更常见病症有相似之处。ABCC6促进ATP的细胞外流，ATP被外核苷酸酶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，针对PXE和GACI仅存在缓解症状的疗法；然而，广泛的研究已经产生了几种治疗PXE和GACI的新方法。这篇综述旨在总结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质（ABCC6、NPP1和TNAP）的治疗策略以及通过各种化合物补充直接抑制钙化。
