@misc{12984,
  abstract     = {{Background
Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder characterized by late onset and progressive calcification of elastic fibers in skin, eyes and the cardiovascular system, exemplifying a model for conditions characterized by soft tissue calcification.
Objective
The aim of our study was to characterize cellular inorganic pyrophosphate (PPi) homeostasis in PXE.
Methods
Gene expression of PPi metabolizing enzymes was determined by quantitative real-time PCR after incubation up to 21 days with or without addition of Na2HPO4. Extracellular and cytosolic PPi concentrations were measured by enzyme-linked bioluminescence assay. ALP and ENPP1 activity was determined spectrophotometrically. We further established a human cell culture model suitable for investigating PXE and related disorders without addition of artificial calcification triggers.
Results
Independently of the experimental conditions, PXE fibroblasts revealed a higher degree of matrix calcification. We observed that matrix calcification was associated with altered gene expression of PPi metabolizing enzymes in PXE fibroblasts. In this context, PXE fibroblasts exhibited significantly higher expression of ALP and OPN and reduced mRNA expression and activity of ENPP1. Here, for the first time cytosolic and extracellular PPi levels were shown to be strongly reduced in PXE fibroblasts. We further showed that PPi concentration in bovine and human sera additives had a strong impact on matrix calcification. In a last experimental line, we demonstrated that addition of PPi analogs reduced matrix calcification of PXE fibroblasts most likely by reducing ALP and OPN mRNA expression, restoring ENPP1 activity and subsequently elevating PPi concentrations.
Conclusion
The results of our study along with recent findings point to the essential role of PPi as the central regulatory metabolites preventing matrix calcification in PXE. But what remains to be determined is the underlying molecular mechanism leading to depletion of PPi in PXE. We further suggest that supplementation of PPi analogs might counteract pathological calcification in PXE and related disorders.}},
  author       = {{Dabisch-Ruthe, Mareike and Kuzaj, Patricia and Götting, Christian and Knabbe, Cornelius and Hendig, Doris}},
  booktitle    = {{Journal of Dermatological Science}},
  issn         = {{1873-569X}},
  keywords     = {{Pseudoxanthoma elasticum, Calcification, Pyrophosphate, Bisphosphonate, ABCC6, Tissue nonspecific alkaline phosphate, Ectonucleotide pyrophosphatase 1}},
  number       = {{2}},
  pages        = {{109--120}},
  publisher    = {{Elsevier }},
  title        = {{{Pyrophosphates as a major inhibitor of matrix calcification in Pseudoxanthoma elasticum}}},
  doi          = {{10.1016/j.jdermsci.2014.04.015}},
  volume       = {{75}},
  year         = {{2014}},
}

@misc{12986,
  abstract     = {{Background
Dysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification.
Methods
In this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.
Results
Gene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE.
Conclusion
Increased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis.}},
  author       = {{Kuzaj, Patricia and Kuhn, Joachim and Dabisch-Ruthe, Mareike and Faust, Isabel and Götting, Christian and Knabbe, Cornelius and Hendig, Doris}},
  booktitle    = {{Lipids in Health and Disease}},
  issn         = {{1476-511X}},
  keywords     = {{Pseudoxanthoma elasticum, ABC transporter, ABCC6, Cholesterol biosynthesis, Atherosclerosis, HMG CoA reductase, SREBP2, PCSK9, LDLR, APOE}},
  number       = {{1}},
  publisher    = {{Biomed Central }},
  title        = {{{ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?}}},
  doi          = {{10.1186/1476-511x-13-118}},
  volume       = {{13}},
  year         = {{2014}},
}