New insights into Pseudoxanthoma elasticum pathogenesis by proteome analysis

Abstract

Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by progressive calcification of elastic fibers leading to cutaneous, retinal, and cardiovascular lesions. Previous studies on PXE skin biopsies suggested that PXE lesions are characterized by deposition of extracellular matrix constituents and/or fragments that favour mineral precipitates as a result of modified cell behaviour. Very recently, we have demonstrated that PXE fibroblasts suffer from mild chronic oxidative stress due to imbalance between production and degradation of oxidant species. The present study was undertaken with the aim to investigate, by proteome analysis, the protein profile of dermal fibroblasts cultured in vitro from 6 healthy individuals and from 6 PXE patients matched for age and gender. Validation of protein changes was done by FACS and Western Blot. Among the identified proteins that appear to significantly change their expression, the majority of them belong to the endoplasmic reticulum‐related pathways and to the oxidative stress response. Moreover, data indicate that, in PXE, calumenin is significantly over‐expressed, thus contributing to inhibition of gamma‐carboxylase activity and to the reduction of the active form of MGP, a potent inhibitor of soft connective tissue calcification. Work supported by grants from EU (GENESKIN #512117, ELASTAGE #18960) and PXE‐International.