ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

Briana K Shimada, Viola Pomozi, Janna Zoll, Sheree Kuo, Ludovic Martin, Olivier Le Saux, Briana K Shimada, Viola Pomozi, Janna Zoll, Sheree Kuo, Ludovic Martin, Olivier Le Saux

Abstract

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.

Keywords: ABCC6; calcification; generalized arterial calcification of infancy; pseudoxanthoma elasticum; pyrophosphate; therapies.

Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Figure 1
Figure 1
The ABCC6 pathway influences calcification and extracellular purinergic metabolism. ABCC6 facilitates the cellular efflux of ATP from liver and other tissues/cells, which is quickly converted to pyrophosphate (PPi), a potent inhibitor of mineralization. Decreased plasma PPi levels cause calcification in PXE and GACI. CD73 activity leads to adenosine production, which affects many biological activities including the inhibition of TNAP synthesis. TNAP degrades PPi into inorganic phosphate (Pi), an activator of calcification, which leads to vascular calcification in CAL JA patients.
Figure 2
Figure 2
Plasma pyrophosphate levels do not correlate with the calcification phenotype in mice. Plasma pyrophosphate levels in Abcc6−/− mice (C57BL/6J background), and in C3H/H1J mice with a naturally occurring Abcc6 mutation are virtually identical and significantly lower than wild type C57BL/6J mice. However, at 12 months of age, Abcc6−/− mice present a much more pronounced vibrissae calcification as shown on this μCT scan rendering (right, arrows). Plasma PPi results are shown as means +SEM. p-values were determined by Student’s t-test. ** p < 0.01, **** p < 0.0001. Derived from [111].
Figure 3
Figure 3
Tested therapeutic Interventions targeting different steps in the ABCC6 pathway to prevent calcification in PXE/GACI. Red boxes point to approaches that were tested in preclinical models and that are currently under human evaluation/trials.

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