Insight into the biological pathways underlying fibromyalgia by a proteomic approach

Abstract

Fibromyalgia (FM) is a form of non-articular rheumatism difficult to diagnose and treat because its etiology remains still elusive. Proteomics makes possible the systematic analysis of hundreds of proteins in clinical samples. Consequently, it has become a key tool for finding altered molecular pathways in different diseases. In this context, the present study analyzes changes in the plasma proteome of patients with FM by nanoscale liquid chromatography coupled to tandem mass spectrometry. Deregulated proteins were studied using Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes. Conventional analytical methods were used to validate selected proteins. We found a total of 33 proteins differentially expressed in patients with FM. Haptoglobin and fibrinogen showed the highest FM/control ratio. IPA analysis revealed that the top enriched canonical pathways were acute-phase response signaling, Liver-X Receptor/Retinoid-X Receptor activation, Farnesoid-X Receptor/Retinoid-X Receptor activation, and coagulation and complement systems. The importance of inflammation in FM was corroborated by the increase in erythrocyte sedimentation rate. In conclusion, our results support the existence of a plasma protein signature of FM that involves different biological pathways all of them related to inflammation, and point to haptoglobin and fibrinogen as plausible biomarker-candidates for future studies.

Significance: The etiology of fibromyalgia (FM) remains elusive making its diagnosis and treatment difficult. The characterization of the proteome signature of this syndrome will improve its understanding. However, to date proteomic analyses in FM are scarce. The goal of the present work is to analyse, for the first time, changes in plasma protein profiles of patients with FM in comparison to control subjects, using label free relative protein quantification by nanoscale liquid chromatography coupled to tandem mass spectrometry. Our data demonstrate the existence of a common protein signature in the plasma of patients with FM that could explain some of the symptoms associated to this syndrome. The analysis of the 33 proteins differentially expressed corroborates the crucial role of inflammation in the pathogenesis of this syndrome. The interplay of the complement and coagulation cascades contributes to the inflammatory process, while the activation of Liver-X Receptor/Retinoid-X Receptor and Farnesoid-X Receptor/Retinoid-X Receptor could attempt to alleviate it. Finally, we have identified two proteins, haptoglobin and fibrinogen, as potential biomarker-candidates of FM for future studies.

Keywords: Fibromyalgia; Inflammation; Pathogenesis; Plasma protein signature.