title: Ectopic calcification in β-thalassemia patients is associated with increased oxidative stress and lower MGP carboxylation.
abstract: A number of beta-thalassemia (β-thal) patients in the course of the disease exhibit ectopic calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from β-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of β-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from β-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of ectopic calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from β-thal PXE-like patients as well as in other diseases leading to ectopic calcification, thus suggesting that can be used as markers of pathologic mineralisation.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; PXELab, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Boraldi
authors.forename: Maria
authors.initials: M
authors.lastname: Garcia-Fernandez
authors.forename: Chiara
authors.initials: C
authors.lastname: Paolinelli-Devincenzi
authors.forename: Giulia
authors.initials: G
authors.lastname: Annovi
authors.forename: Leon
authors.initials: L
authors.lastname: Schurgers
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.forename: Paolo
authors.initials: P
authors.lastname: Cianciulli
authors.forename: Ivonne
authors.initials: I
authors.lastname: Ronchetti
authors.forename: Daniela
authors.initials: D
authors.lastname: Quaglino
mesh_terms: D000328:Adult; D062107:Advanced Oxidation Protein Products / Q000378:metabolism; D015153:Blotting, Western; D002114:Calcinosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002264:Carboxylic Acids / Q000378:metabolism*; D019175:DNA Methylation; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology*; D004549:Elastin / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress; D011561:Pseudoxanthoma Elasticum / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism; D017086:beta-Thalassemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000097568:Matrix Gla Protein
chemical_list: D062107:Advanced Oxidation Protein Products; D002135:Calcium-Binding Proteins; D002264:Carboxylic Acids; D004549:Elastin; D016326:Extracellular Matrix Proteins; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D008054:Lipid Peroxides; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D014812:Vitamin K; D000097568:Matrix Gla Protein
keywords: Beta-thalassemia; Ectopic calcification; Elastin; Matrix Gla protein; Oxidative stress