title: Targeted Metabolic Profiling of the Tg197 Mouse Model Reveals Itaconic Acid as a Marker of Rheumatoid Arthritis.
abstract: Rheumatoid arthritis is a progressive, highly debilitating disease where early diagnosis, enabling rapid clinical intervention, would provide obvious benefits to patients, healthcare systems, and society. Novel biomarkers that enable noninvasive early diagnosis of the onset and progression of the disease provide one route to achieving this goal. Here a metabolic profiling method has been applied to investigate disease development in the Tg197 arthritis mouse model. Hind limb extract profiling demonstrated clear differences in metabolic phenotypes between control (wild type) and Tg197 transgenic mice and highlighted raised concentrations of itaconic acid as a potential marker of the disease. These changes in itaconic acid concentrations were moderated or indeed reversed when the Tg197 mice were treated with the anti-hTNF biologic infliximab (10 mg/kg twice weekly for 6 weeks). Further in vitro studies on synovial fibroblasts obtained from healthy wild-type, arthritic Tg197, and infliximab-treated Tg197 transgenic mice confirmed the association of itaconic acid with rheumatoid arthritis and disease-moderating drug effects. Preliminary indications of the potential value of itaconic acid as a translational biomarker were obtained when studies on K4IM human fibroblasts treated with hTNF showed an increase in the concentrations of this metabolite.
authors.affiliation: Bioscience, Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.|Department of Chemistry, Aristotle University of Thessaloniki , Thessaloniki 541 24, Greece.
authors.forename: Filippos
authors.initials: F
authors.lastname: Michopoulos
authors.affiliation: Biomedcode Hellas SA, 34 Fleming Street, Vari 16672, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Karagianni
authors.affiliation: Bioscience, Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Nichola M
authors.initials: NM
authors.lastname: Whalley
authors.affiliation: Discovery Science, iMED, AstraZeneca, Cambridge CB4 0FZ, United Kingdom.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Firth
authors.affiliation: Biomedical Siences Research Center "Alexander Fleming", 34 Fleming Street, Vari 16672, Greece.|Department of Biology, University of Crete , Heraklion 741 00, Greece.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Nikolaou
authors.affiliation: Department of Surgery and Cancer, Imperial College , London SW7 2AZ, United Kingdom.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.affiliation: Bioscience, Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Critchlow
authors.affiliation: Biomedical Siences Research Center "Alexander Fleming", 34 Fleming Street, Vari 16672, Greece.|Department of Physiology, Faculty of Medicine, National and Kapodistrian University of Athens , Athens 11527, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.affiliation: Department of Chemistry, Aristotle University of Thessaloniki , Thessaloniki 541 24, Greece.
authors.forename: Georgios A
authors.initials: GA
authors.lastname: Theodoridis
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000175:diagnosis*; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D013386:Succinates / Q000032:analysis* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; C005229:itaconic acid
keywords: biomarker; intracellular metabolites; mass spectrometry; metabolomics; rheumatoid arthritis; targeted analysis