ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

International Journal of Molecular Sciences

BrianaK. Shimada¹  Janna Zoll¹  Olivier Le Saux¹  Sheree Kuo²  Viola Pomozi³  Ludovic Martin⁴ 

[1] Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96817, USA;Department of Pediatrics, Kapi’olani Medical Center for Women and Children, University of Hawaii, Honolulu, HI 96826, USA;Institute of Enzymology, RCNS, Hungarian Academy of Sciences, 1117 Budapest, Hungary;PXE Consultation Center, MAGEC Reference Center for Rare Skin Diseases, Angers University Hospital, 49100 Angers, France;

关键词: calcification;    ABCC6;    pseudoxanthoma elasticum;    generalized arterial calcification of infancy;    pyrophosphate;    therapies;   

DOI  :  10.3390/ijms22094555

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown