Pathologic mineralization of the skin and vascular connective tissues is the hallmark of certain single gene heritable disorders. Pseudoxanthoma elasticum (PXE), caused in most cases by loss-of-function mutations in the ABCC6 gene, serves as a prototype of heritable multi-system ectopic mineralization disorders with Control calcium and phosphate homeostasis. Generalized arterial calcification of infancy (GACI), caused in most cases by mutations in the ENPP1 gene, has overlapping phenotypic features with PXE. However, it was recently shown that PXE and GACI in some cases can also be caused by mutations in either ENPP1 or ABCC6, respectively. These observations suggested the possibility of shared pathomechanistic pathways for these conditions, and specifically, studies in these diseases and their corresponding mouse models revealed reduced plasma levels of inorganic pyrophosphate, a powerful inhibitor of mineralization. Consequently, the results suggested that insufficient inorganic pyrophosphate in the blood circulation underlies ectopic mineralization in both conditions. Towards development of treatment for these ectopic mineralization disorders, we have performed studies targeting plasma pyrophosphate deficiency through direct supplementation of inorganic pyrophosphate, or administration of stable, non-hydrolyzable pyrophosphate analogues, bisphosphonates, for treatment of these ectopic mineralization disorders in mouse models of PXE and GACI, Abcc6-/- and Enpp1asj. These approaches resulted in reduced ectopic mineralization in these mice, suggesting novel treatment modalities for these currently intractable diseases.

Targeting Plasma Pyrophosphate Deficiency in Mouse Models of Heritable Ectopic Mineralization Disorders – PXE and GACI