Virgil Tamatey (1,2) Martin Várhegyi (1,3) Dániel Kovács (1), Dénes Juhász (4), Anikó Ilona Nagy (4), Tamás Arányi (1), Flora Szeri (1)
Affiliation(s):
1. HUN-REN Research Centre for Natural Sciences, Institute of Molecular Life Sciences, Budapest, Hungary
2. Doctoral School of Biology, ELTE, Budapest, Hungary
3. Doctoral School of Semmelweis University, Budapest, Hungary
4. Heart and Vascular Center, Semmelweis University, Budapest, Hungary
Tissue nonspecific alkaline phosphatase is primarily expressed in the liver and bone but is also present in the circulation in a soluble form. Serum alkaline phosphatase (AP) cleaves the mineralization inhibitor inorganic pyrophosphate (PPi) to inorganic phosphate (Pi), a building block for biominerals. Plasma PPi is an essential inhibitor of ectopic calcification in acquired conditions, e.g., chronic kidney disease, and in rare hereditary mineralization disorders such as pseudoxanthoma elasticum (PXE). PXE manifests due to loss of function mutations in ABCC6, resulting in 70-50% reduced plasma PPi levels compared to controls. As the kinetics and determinants of the extracellular PPi homeostasis are largely unknown, we investigated the circulatory AP-PPi-Pi axis in Abcc6-/- and wild-type (WT) mice and control human individuals with no CT-detectable ectopic calcification.
We found profound changes in the AP activity, PPi, and Pi levels during maturation and aging in mice. AP activity is high at weaning but drastically declines at a young age, paralleled with up to a twofold increase in plasma PPi levels in both WT and Abcc6-/- strains. Later in life, plasma PPi of Abcc6-/- mice steadily increase while Pi, and consequently Pi/PPi ratio, an important determinant of the calcification propensity, decreases. In the Abcc6-/- mice, AP activity exhibits a strong negative and modest positive correlation with PPi and Pi levels, respectively, up to 600 days; thus, the Pi/PPi ratio strongly correlates to serum AP activity.
Human control individuals with no CT-detectable coronary and heart valve calcification exhibit similar kinetics, with a significant age-dependent increase of plasma PPi and a decrease of the Pi/PPi ratio. Moreover, plasma PPi levels and circulatory Pi/PPi ratio strongly correlate to AP activity.
Our data hints that AP activity plays a role in determining circulatory PPi and Pi levels in mice and humans under certain circumstances. Consequently, Pi/PPi balance is altered during the lifetime, favoring mineralization in the young and acting against calcification in the elderly, by a putative preventive mechanism likely independent of ABCC6 function.