title: Matrix gla protein and alkaline phosphatase are differently modulated in human dermal fibroblasts from PXE patients and controls.
abstract: Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Boraldi
authors.forename: Giulia
authors.initials: G
authors.lastname: Annovi
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Tommaso
authors.initials: T
authors.lastname: Trenti
authors.forename: Roberta
authors.initials: R
authors.lastname: Tiozzo
authors.forename: Deanna
authors.initials: D
authors.lastname: Guerra
authors.forename: Daniela
authors.initials: D
authors.lastname: Quaglino
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000933:Antifibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002114:Calcinosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007978:Levamisole / Q000494:pharmacology; D008875:Middle Aged; D010710:Phosphates / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014812:Vitamin K / Q000493:pharmacokinetics / Q000494:pharmacology*; D000097568:Matrix Gla Protein
chemical_list: D000276:Adjuvants, Immunologic; D000469:Alkaline Phosphatase; D000933:Antifibrinolytic Agents; D002118:Calcium; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D007978:Levamisole; D010710:Phosphates; D014812:Vitamin K; D000097568:Matrix Gla Protein