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Am J Pathol. 2017 Jun;187(6):1258-1272. doi: 10.1016/j.ajpath.2017.02.009. Epub 2017 Apr 14.

Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice.

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Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, Pennsylvania.
Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Université Bretagne-Loire, Integrated Neurovascular and Mitochondrial Biology, National Center for Scientific Research 6214/INSERM 1083, Angers, France; University Hospital Angers, Center for PXE Consultation, Angers, France.
Institut für Integrative und Experimentelle Genomik Universität zu Lübeck, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany; University Heart Centre Lübeck, Universität zu Lübeck, Lübeck, Germany.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii. Electronic address:


Soft tissue calcification occurs in several common acquired pathologies, such as diabetes and hypercholesterolemia, or can result from genetic disorders. ABCC6, a transmembrane transporter primarily expressed in liver and kidneys, initiates a molecular pathway inhibiting ectopic calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a major calcification inhibitor. Heritable mutations in ABCC6 underlie the incurable calcification disorder pseudoxanthoma elasticum and some cases of generalized arterial calcification of infancy. Herein, we determined that the administration of PPi and the bisphosphonate etidronate to Abcc6-/- mice fully inhibited the acute dystrophic cardiac calcification phenotype, whereas alendronate had no significant effect. We also found that daily injection of PPi to Abcc6-/- mice over several months prevented the development of pseudoxanthoma elasticum-like spontaneous calcification, but failed to reverse already established lesions. Furthermore, we found that the expression of low amounts of the human ABCC6 in liver of transgenic Abcc6-/- mice, resulting in only a 27% increase in plasma PPi levels, led to a major reduction in acute and chronic calcification phenotypes. This proof-of-concept study shows that the development of both acute and chronic calcification associated with ABCC6 deficiency can be prevented by compensating PPi deficits, even partially. Our work indicates that PPi substitution represents a promising strategy to treat ABCC6-dependent calcification disorders.

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