Plasma PPi Deficiency is the Major, But Not the Exclusive, Cause of Ectopic Mineralization in an Abcc6(-/-) Mouse Model of PXE.

Jingyi Zhao
Joshua Kingman
John P Sundberg, The Jackson Laboratory
Jouni Uitto
Qiaoli Li


Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, is caused in most cases by inactivating mutations in the ABCC6 gene. It was recently discovered that absence of ABCC6-mediated ATP release from the liver and consequently reduced plasma PPi levels underlie PXE. This study examined whether reduced levels of circulating PPi, an anti-mineralization factor, is the sole mechanism of PXE. The Abcc6(-/-) and Enpp1(asj) mice were crossed with transgenic mice expressing human ENPP1, an ectonucleotidase which generates PPi from ATP. We generated Abcc6(-/-) and Enpp1(asj) mice, either wild type or hemizygous for human ENPP1. Plasma levels of PPi and the degree of ectopic mineralization were determined. Overexpression of human ENPP1 in Enpp1(asj) mice normalized plasma PPi levels to that of wild type mice, and consequently, completely prevented ectopic mineralization. These changes were accompanied with restoration of their bone microarchitecture. In contrast, while significantly reduced mineralization was noted in Abcc6(-/-) mice expressing human ENPP1, small mineralization foci were still evident despite increased plasma PPi levels. These results suggest that PPi is the major mediator of ectopic mineralization in PXE, but there might be an alternative, as-yet unknown mechanism, independent of PPi, by which ABCC6 prevents ectopic mineralization under physiologic conditions.