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

Viola Pomozi, Christopher Brampton, Koen van de Wetering, Janna Zoll, Bianca Calio, Kevin Pham, Jesse B. Owens, Joel Marh, Stefan Moisyadi, A. Váradi, Ludovic Martin, Carolin Bauer, Jeanette Erdmann, Zouhair Aherrahrou, Olivier Le Saux

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1258-1272
Number of pages15
JournalAmerican Journal of Pathology
Volume187
Issue number6
DOIs
Publication statusPublished - Jun 1 2017

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Pseudoxanthoma Elasticum
Etidronic Acid
Phenotype
Alendronate
Inborn Genetic Diseases
Liver
Diphosphonates
Hypercholesterolemia
Transgenic Mice
Adenosine Triphosphate
Pathology
Kidney
Mutation
Injections
diphosphoric acid
Arterial calcification of infancy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Pomozi, V., Brampton, C., van de Wetering, K., Zoll, J., Calio, B., Pham, K., ... Le Saux, O. (2017). Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice. American Journal of Pathology, 187(6), 1258-1272. https://doi.org/10.1016/j.ajpath.2017.02.009

Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice. / Pomozi, Viola; Brampton, Christopher; van de Wetering, Koen; Zoll, Janna; Calio, Bianca; Pham, Kevin; Owens, Jesse B.; Marh, Joel; Moisyadi, Stefan; Váradi, A.; Martin, Ludovic; Bauer, Carolin; Erdmann, Jeanette; Aherrahrou, Zouhair; Le Saux, Olivier.

In: American Journal of Pathology, Vol. 187, No. 6, 01.06.2017, p. 1258-1272.

Research output: Contribution to journalArticle

Pomozi, V, Brampton, C, van de Wetering, K, Zoll, J, Calio, B, Pham, K, Owens, JB, Marh, J, Moisyadi, S, Váradi, A, Martin, L, Bauer, C, Erdmann, J, Aherrahrou, Z & Le Saux, O 2017, 'Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice', American Journal of Pathology, vol. 187, no. 6, pp. 1258-1272. https://doi.org/10.1016/j.ajpath.2017.02.009
Pomozi, Viola ; Brampton, Christopher ; van de Wetering, Koen ; Zoll, Janna ; Calio, Bianca ; Pham, Kevin ; Owens, Jesse B. ; Marh, Joel ; Moisyadi, Stefan ; Váradi, A. ; Martin, Ludovic ; Bauer, Carolin ; Erdmann, Jeanette ; Aherrahrou, Zouhair ; Le Saux, Olivier. / Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice. In: American Journal of Pathology. 2017 ; Vol. 187, No. 6. pp. 1258-1272.
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