THE EFFECTS OF TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE (TNAP) INHIBITORS ON CALCIFICATION AND INORGANIC PYROPHOSPHATE LEVELS IN Abcc6-/- MICE

Abstract

Pseudoxanthoma Elasticum (PXE) is a genetic disorder which leads to calcification of the elastin, causing a variety of symptoms. Calcification is the main cause of other genetic disorders (table 1) and plays a secondary role in other disorders (De Vilder et al. 2015). There are no treatments to prevent or slow the calcification in these disorders. Pyrophosphate (PPᵢ) is an inhibitor of calcification. Adenosine triphosphate (ATP) is secreted from the liver through the Abcc6 transport protein (Jansen et al. 2013, 2014). Without this ATP, PPᵢ is reduced, leading to calcification. Tissue-nonspecific alkaline phosphatase (TNAP) breaks down PPi to phosphate (Pi), increasing calcification. Inhibiting TNAP may increase the PPi and reduce the Pi. This will reduce the calcification, shown by Sheen et.al (2015) in mice genetically programmed to have excess TNAP. To test whether a TNAP inhibitor reduces calcification, the TNAP inhibitor SBI-425 (Gahl, W. et al. 2016), will be given to mice lacking the transporter (Abcc6-/- mice). Pyrophosphate, liver enzymes, and TNAP will be measured during the study. Calcification will be measured in the vibrissae and aorta. Bone scans and histomorphometric studies will be conducted. All results will be compared to the Abcc6-/- mice not given the inhibitor and Abcc6+/+ control mice.