An inflammatory arthritis-associated metabolite biomarker pattern revealed by 1H NMR spectroscopy.
Rheumatoid arthritis, a debilitating, systemic inflammatory joint disease, is likely accompanied by alterations in circulating metabolites. Here, an 1H NMR spectroscopy-based metabolomics approach was developed to establish a metabolic 'biomarker pattern' in a model of rheumatoid arthritis, the K/BxN transgenic mouse. Sera obtained from arthritic K/BxN mice (N = 15) and a control population (N = 19) having the same genetic background, but lacking the arthritogenic T-cell receptor KRN transgene, were compared by 1H NMR spectroscopy. A unique method was developed by combining technologies such as ultrafiltration to remove proteins from serum samples, quantitative 'targeted profiling' of known metabolites, pseudo-quantitative profiling of unknown resonances, a supervised O-PLS-DA pattern recognition analysis, and a metabolic-pathway based network analysis for interpretation of results. In total, 88 spectral features were profiled (59 metabolites and 28 unknown resonances). A highly significant subset of 18 spectral features (15 known compounds and 3 unknown resonances) was identified (p = 0.00075 using MANOVA) that we term a 'metabolic bioprofile'. We identified metabolites relating to nucleic acid, amino acid, and fatty acid metabolism, as well as lipolysis, reactive oxygen species generation, and methylation. Pathway analysis suggested a shift from metabolites involved in numerous reactions (hub-metabolites) toward intermediates and metabolic endpoints associated with arthritis. The results attest to the metabolic complexity of systemic inflammation and to the power of the experimental approach for identifying a wide variety of disease-associated marker candidates. The diagnostic and prognostic implications of monitoring a spectrum of metabolic events simultaneously using serum samples is discussed with respect to the potential for individualized medicine.
Weljie
Aalim M
AM
Metabolomics Research Centre, Department of Biological Sciences, Department of Biochemistry and Molecular Biology, and the McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Dowlatabadi
Reza
R
Miller
B Joan
BJ
Vogel
Hans J
HJ
Jirik
Frank R
FR
D000818:Animals; D001168:Arthritis / Q000097:blood* / Q000175:diagnosis* / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000097:blood*; D015415:Biomarkers / Q000737:chemistry*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D007249:Inflammation / Q000097:blood*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D040901:Proteomics / Q000379:methods*
D015415:Biomarkers