The Liver Regulates Tissue Calcification in Pseudoxanthoma Elasticum

Pseudoxanthoma Elasticum (PXE) is a rare disease caused by loss of function of the gene Abcc6 and characterized by ectopic calcification of multiple tissues including the heart and vasculature. The physiological reasons underlying ectopic calcification in PXE remain unclear. We created a robust model of ectopic cardiac calcification where animals globally deficient in the gene Abcc6 developed extensive mineralization of the heart within 3 days of cardiac injury. To obtain insight into the underlying mechanisms of ectopic cardiac calcification in PXE, we generated animals with cardiomyocyte specific deletion of Abcc6 but did not observe any calcification, suggesting that Abcc6 was acting in a myocyte non-autonomous manner to cause calcification. Inflammation is known to play a key role in ectopic calcification of the cardiovascular system but bone marrow transplantation experiments from wild type animals into Abcc6 deficient animals did not rescue the calcific phenotype. However, tissue specific deletion of Abcc6 in the liver was sufficient to cause post injury cardiac calcification, suggesting a role of the liver in driving ectopic calcification of distant tissues. Metabolomics and gene expression analysis of animals globally deficient or with liver specific deletion of Abcc6 demonstrated deficiencies in nucleotide metabolism and pathways regulating cellular energetics. We show that such metabolic abnormalities are associated with profound abnormalities in cellular respiration in the injured cardiac tissue. Functional abnormalities in cellular respiration in the injured heart were similar in animals globally deficient in Abcc6 or with liver specific deletion demonstrating that abcc6 regulates cellular respiration in the heart in a liver cell autonomous manner. Notably calcification of the heart in Abcc6 deficient states was not secondary to induction of an osteogenic gene expression program in the heart but occurred rapidly secondary to dystrophic calcification with initial mineralization deposits noted with the cardiac muscle. Treatment with clodronate, a clinically approved bisphosphonate that prevents growth of mineralization was sufficient to rescue the phenotype of ectopic cardiac calcification in Abcc6 deficient states. Taken together, these observations highlight the role of the liver in regulating cardiac metabolic and mitochondrial function and causing ectopic calcification in Abcc6 deficient states.