Large-scaled metabolic profiling of human dermal fibroblasts derived from pseudoxanthoma elasticum patients and healthy controls

Patricia Kuzaj; Joachim Kuhn; Ryan D Michalek; Edward D Karoly; Isabel Faust; Mareike Dabisch-Ruthe; Cornelius Knabbe; Doris Hendig

doi:10.1371/journal.pone.0108336

Large-scaled metabolic profiling of human dermal fibroblasts derived from pseudoxanthoma elasticum patients and healthy controls

PLoS One. 2014 Sep 29;9(9):e108336. doi: 10.1371/journal.pone.0108336. eCollection 2014.

Authors

Patricia Kuzaj¹, Joachim Kuhn¹, Ryan D Michalek², Edward D Karoly², Isabel Faust¹, Mareike Dabisch-Ruthe¹, Cornelius Knabbe¹, Doris Hendig¹

Affiliations

¹ Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
² Metabolon, Inc., Durham, North Carolina, United States of America.

Abstract

Mutations in the ABC transporter ABCC6 were recently identified as cause of Pseudoxanthoma elasticum (PXE), a rare genetic disorder characterized by progressive mineralization of elastic fibers. We used an untargeted metabolic approach to identify biochemical differences between human dermal fibroblasts from healthy controls and PXE patients in an attempt to find a link between ABCC6 deficiency, cellular metabolic alterations and disease pathogenesis. 358 compounds were identified by mass spectrometry covering lipids, amino acids, peptides, carbohydrates, nucleotides, vitamins and cofactors, xenobiotics and energy metabolites. We found substantial differences in glycerophospholipid composition, leucine dipeptides, and polypeptides as well as alterations in pantothenate and guanine metabolism to be significantly associated with PXE pathogenesis. These findings can be linked to extracellular matrix remodeling and increased oxidative stress, which reflect characteristic hallmarks of PXE. Our study could facilitate a better understanding of biochemical pathways involved in soft tissue mineralization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcinosis / pathology*
Cell Line
Dermis / cytology
Dermis / metabolism*
Dermis / pathology
Dipeptides / biosynthesis
Elastic Tissue / pathology*
Extracellular Matrix / metabolism
Fatty Acids / biosynthesis
Fatty Acids / classification
Fibroblasts / metabolism
Gene Expression
Glycerophospholipids / biosynthesis
Glycerophospholipids / classification
Guanine / metabolism
HEK293 Cells
Humans
Metabolomics
Multidrug Resistance-Associated Proteins / biosynthesis
Multidrug Resistance-Associated Proteins / genetics*
Mutation / genetics
Oxidative Stress
Pantothenic Acid / metabolism
Pseudoxanthoma Elasticum / genetics
Pseudoxanthoma Elasticum / metabolism*
Pseudoxanthoma Elasticum / pathology
Purines / metabolism
RNA Interference
RNA, Small Interfering

Substances

ABCC6 protein, human
Dipeptides
Fatty Acids
Glycerophospholipids
Multidrug Resistance-Associated Proteins
Purines
RNA, Small Interfering
Pantothenic Acid
Guanine

Grants and funding

Parts of this work were funded by the German Research Foundation (DFG, He 5900/2-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.