Abstract

BackgroundInflammatory arthritis (IA) is an immunological disorder in which loss of immune tolerance to endogenous self-antigens perpetuates synovitis and eventual destruction of the underlying cartilage and bone. Pathological changes in the joint are expected to be represented by synovial fluid (SF) proteins and peptides. In the present study, a mass spectrometry-based approach was utilized for the identification of key protein and peptide mediators of IA.MethodsAge-matched SF samples from 10 rheumatoid arthritis patients, 10 psoriatic arthritis patients and 10 cadaveric controls were subjected to an integrated proteomic and peptidomic protocol using liquid chromatography tandem mass spectrometry. Significant differentially abundant proteins and peptides were identified between cohorts according to the results of a Mann–Whitney U test coupled to the Benjamini–Hochberg correction for multiple hypothesis testing. Fold change ratios were computed for each protein and peptide according to their log-transformed extracted ion current. Pathway analysis and antimicrobial peptide (AMP) prediction were conducted to clarify the pathophysiological relevance of identified proteins and peptides to IA.ResultsWe determined that 144 proteins showed significant differential abundance between the IA and control SF proteomes, of which 11 protein candidates were selected for future follow-up studies. Similar analyses applied to our peptidomic data identified 15 peptide sequences, originating from 4 protein precursors, to have significant differential abundance in IA compared to the control SF peptidome. Pathway enrichment analysis of the IA SF peptidome along with AMP prediction suggests a possible mechanistic role of microbes in eliciting an immune response which drives the development of IA.ConclusionsThe discovery-phase data generated herein has provided a basis for the identification of candidates with the greatest potential to serve as novel serum biomarkers specific to inflammatory arthritides. Moreover, these findings facilitate the understanding of possible disease mechanisms specific to each subtype.

Highlights

  • Inflammatory arthritis (IA) is characterized by synovial hyperplasia leading to degradation of adjacent articular cartilage and bone [1]

  • When assessing each cohort individually, 377 unique proteins were identified in Rheumatoid arthritis (RA) patient samples, 369 unique proteins were identified in psoriatic arthritis (PsA) patient samples and 399 proteins were identified in control patient samples

  • Chronic inflammation in IA is orchestrated by a complex network of signaling pathways which are expected to be represented in the protein and peptide expression patterns of synovial fluid (SF)

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Summary

Introduction

Inflammatory arthritis (IA) is characterized by synovial hyperplasia leading to degradation of adjacent articular cartilage and bone [1]. IA is a multifactorial disease driven by the complex interplay of both genetics and the environment. The exact etiology of IA is still poorly understood with studies aimed at delineating the molecular pathways driving loss of immunological tolerance to the body’s self-antigens. Alterations to the adaptive and innate immune system perpetuate systemic inflammation and lead to an elevated risk of developing comorbid conditions such as cardiovascular disease, metabolic syndrome, diabetes and depression [7, 8]. Inflammatory arthritis (IA) is an immunological disorder in which loss of immune tolerance to endogenous self-antigens perpetuates synovitis and eventual destruction of the underlying cartilage and bone. A mass spectrometry-based approach was utilized for the identification of key protein and peptide mediators of IA

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