Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling in the pathogenesis of pseudoxanthoma elasticum

• Published in: Proteomics. Clinical applications Vol. 3; no. 9; pp. 1084 - 1098
• Main Authors: Boraldi, Federica, Annovi, Giulia, Guerra, Deanna, Paolinelli DeVincenzi, Chiara, Garcia‐Fernandez, Maria Inmaculada, Panico, Fulvio, De Santis, Giorgio, Tiozzo, Roberta, Ronchetti, Ivonne, Quaglino, Daniela
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag 01-09-2009; Wiley
• Subjects: Biological and medical sciences; Diverse techniques; Ectopic calcification; Elastin; Fibroblast proteome; Fundamental and applied biological sciences. Psychology; Medical sciences; Molecular and cellular biology; MRP6; PXE; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Oxidative stress; Pathogenesis; Elastin; Vitamin; Proteome; Fibroblast proteome; Profile; Protein; MRP6; Ectopic calcification; Analysis; Proteomics; Calcification; Pseudoxanthoma elasticum; Ectopia; Recycling; PXE; Fibroblast
• DOI: 10.1002/prca.200900007
• EISSN: 1862-8354
• ISSN: 1862-8346

Pseudoxanthoma elasticum (PXE) is a genetic disorder associated to mutations in the ABCC6 gene; however, the pathogenetic mechanisms leading to elastic fibre calcifications and to clinical manifestations are still unknown. Dermal fibroblasts, directly involved in the production of the extracellular milieu, have been isolated from healthy subjects and from patients affected by PXE, cultured in vitro and characterized for their ability to produce reactive oxygen species, for structural and functional properties of their cell membranes, for changes in their protein profile. Data demonstrate that oxidative stress has profound and endurable consequences on PXE fibroblast phenotype being responsible for: reduced levels of global DNA methylation, increased amount of carbonylated proteins and of lipid peroxidation products, altered structural properties of cell membranes, modified protein expression. Data shed new light on the pathogenetic pathways in PXE, by identifying a network of proteins affecting elastic fibre calcification through inefficient vitamin K recycling, and highlight the role of differentially expressed proteins as targets for validating the efficacy of future therapeutic strategies aiming to delay and/or revert the pathologic phenotype of PXE fibroblasts. Moreover, data open new perspectives for investigating PXE‐like phenotypes in the absence of ABCC6 mutations.