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Title: Protein damage markers in diagnosis, progression and treatment of arthritis
Author: Ahmed, Usman
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2013
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Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases associated with damage and proteolytic loss of protein from affected joints. The types and amounts of protein damage and related proteolytic debris in synovial fluid and released into the circulation has not been studied comprehensively. The aim of this study is to quantify levels of protein damage in a cross-sectional pilot study of synovial fluid and plasma of patients with early-stage OA (eOA) and RA (eRA), and self-resolving arthritis (non-RA), and compare these with patients with advanced stage OA (aOA) and RA (aRA), and with plasma of healthy subjects. Patients with eOA, aOA, eRA and non-RA were recruited by collaborating clinicians from rheumatology and orthopaedic clinics in hospitals in Coventry, Birmingham, Ipswich and Exeter and synovial fluid and plasma samples collected from patients with consent. Major chemically-defined markers of protein damage by glycation, oxidation, nitration and citrullination were quantified in sample protein and in ultrafiltrate (glycated, oxidized and nitrated amino acids) by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Hydroxyproline was also determined. Our results demonstrated varying degrees of changes within protein damage marker concentrations across all subject groups, however there were many significant changes. Protein oxidation and advanced glycation endproducts were noted to be elevated both synovial fluid and plasma of patients with aRA and aOA with elevated levels also noted in eRA and eOA synovial fluid. Citrullinated proteins were noted to be markedly increased in plasma protein in both eOA and eRA. Markers of nitration were also elevated in non-RA plasma there was a decrease in nitration despite increases in glycation and oxidation. Changes in damaged amino acids in synovial fluid and plasma were similar across all patients. In aRA and aOA there was increased amino acid oxidation and advanced glycation and decreased amino acid nitration. There was also increased hydroxyproline in plasma. In eRA and eOA there was increased amino acid oxidation and increased advanced glycation in eRA (Nω-carboxymethylarginine). Changes in amino acid oxidation and advanced glycation were restricted to plasma in non-RA. The changes in protein damage and citrullination were characteristic “signatures” that allowed production of data trained algorithms with over ≥ 97% specificity and sensitivity for diagnosis and discrimination of eOA, eRA and non-RA. This study provides the first comprehensive attempt at quantification of protein damage markers in joint disease using LC-MS/MS techniques – a gold standard. The improved characterisation of protein damage and related metabolites will likely advance understanding of early-stage processes in joint degeneration which is still poorly understood and may provide novel plasma biomarkers for diagnosis and risk of disease progression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; R Medicine (General) ; RC Internal medicine