Targeted Metabolic Profiling of the Tg197 Mouse Model Reveals Itaconic Acid as a Marker of Rheumatoid Arthritis

Targeted Metabolic Profiling of the Tg197 Mouse Model Reveals Itaconic Acid as a Marker of Rheumatoid Arthritis

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 di...

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Bibliographic Details
Published in:Journal of proteome research Vol. 15; no. 12; pp. 4579 - 4590
Main Authors: Michopoulos, Filippos, Karagianni, Niki, Whalley, Nichola M, Firth, Mike A, Nikolaou, Christoforos, Wilson, Ian D, Critchlow, Susan E, Kollias, George, Theodoridis, Georgios A
Format: Journal Article
Language:English
Published: United States American Chemical Society 02-12-2016
Subjects:
Animals
Arthritis, Rheumatoid - diagnosis
Biomarkers - analysis
Cell Line
Fibroblasts - drug effects
Fibroblasts - metabolism
Humans
Metabolomics - methods
Mice
Mice, Transgenic
Succinates - analysis
Succinates - metabolism
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - pharmacology
intracellular metabolites
mass spectrometry
targeted analysis
biomarker
metabolomics
rheumatoid arthritis
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Summary: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.
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ISSN:1535-3893
1535-3907
DOI:10.1021/acs.jproteome.6b00654