Plasma inorganic pyrophosphate and alkaline phosphatase in patients with pseudoxanthoma elasticum

Abstract

Background: Inorganic pyrophosphate (PPi) plays a major role inhibiting dystrophic calcification. The aim was to analyze levels of PPi in patients having pseudoxanthoma elasticum (PXE), and controls as well as the enzymes who regulate the PPi plasma concentration.Methods: We collected fasting blood samples from PXE patients and age-and sex-matched controls in ethylenediamine tetraacetic acid (EDTA) and citrate-theophylline-adenosine-dipyridamole (CTAD) containing tubes. We measured PPi, ENPP1 mass and activity, alkaline phosphatase (AP) and tissue nonspecific alkaline phosphatase (TNAP), CD73 and Human Platelet Factor-4 (CXCL4).Results: PPi in EDTA and CTAD samples were lower in PXE subjects than in controls (1.11±0.26 vs.1.43±0.41 μM/L and 0.35±0.15 vs. 0.61±0.18 μM/L respectively, P<0.05). TNAP and liver TNAP activities were also higher in PXE than in controls (80.3±27.0 vs. 63.3±16.4 UI/L and 25.6±14.9 vs. 12.9±9.2 UI/L respectively, P<0.05). ENPP1 mass and activity as well as CD73 were almost identical. There was a weak but significant inverse correlation between TNAP activity and PPi levels (Pearson correlation −0.379, P<0.05) in both groups.Conclusions: High TNAP activity seems to contribute to low plasma levels of PPi in subjects with PXE, reinforcing the idea that pharmacological reduction of TNAP activity may help to reduce dystrophic calcification in PXE patients.

From membrane to mineralization: the curious case of the ABCC6 transporter

“…The latter may partly contribute to the decreased PPi plasma levels observed in PXE patients, similar to what has been suggested for higher TNAP activity seen in PXE patients. Indeed, S anchez-T evar et al showed that TNAP activity was inversely correlated with plasma levels of PPi [50].…”

“…Indeed, Sánchez‐Tévar et al . showed that TNAP activity was inversely correlated with plasma levels of PPi [50].…”

“…Untargeted metabolomics of hABCC6 and rABCC6 transfected HEK293 cells demonstrated significant changes in various nucleoside, nucleoside mono-, di-, and triphosphate and nucleotide sugar levels in the cell medium [49]. Moreover, ABCC6 deficiency was then determined to lead to significant reductions in plasma PPi levels in humans (AE60-43% decrease), mice (AE60% decrease), and rats (AE60% decrease) [49][50][51][52]. Of note, in rats, kidneys were also found to excrete PPi albeit at~10% of the hepatic output [52].…”

Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

“…The latter is a powerful physiological antimineralization factor which interferes with hydroxyapatite crystal growth by binding to the initial nucleus of mineralization and preventing calcium phosphate deposition. In patients with PXE with nonfunctional ABCC6, the plasma levels of PPi are reduced to about 40% of the level in normal healthy individuals, which is reproducibly in the range of 1 µM measured by using a number of analytical techniques [ 12 , 13 ]. Reduced PPi levels then allow the growth of calcium hydroxyapatite crystal deposits on the surfaces of the extracellular matrix, particularly the elastic structures.…”

Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway

“…The human Abcc6 gene belongs to the ABCC family and codifies for the MRP6 protein, mainly expressed at the basolateral membrane of hepatocytes [4]. More than 300 mutations in Abcc6 such as deletions, insertions, or substitutions, mostly occurring in the sequence encoding the nucleotide binding domains, are associated with the Pseudoxanthoma elasticum, an autosomal recessive disease characterized by a progressive ectopic calcification [5][6][7]. Studies aimed at understanding the molecular mechanisms underlying the observed phenotype have shown that ABCC6 contributes to the outflow of ATP from cells [8,9].…”