001 NOVEL BIOMARKERS OF KNEE OSTEOARTHRITIS IDENTIFIED USING METABOLIC PROFILING

Abstract

Purpose: There is a pressing need to develop reliable molecular biomarkers that can inform on the process of joint destruction in osteoarthritis (OA). Such biomarkers could aid in drug development by identifying fast progressors and early response to therapy. Recent advance in metabolomics (the quantitative analysis of all metabolites present within a biological sample) has opened new avenues for biomarker identification. The aim of the study, therefore, was to identify serum metabolic biomarkers for OA using a metabolomics approach. Methods: 123 knee OA cases and 299 controls were selected from the TwinsUK cohort. Knee OA was defined as either radiographic, self-reported OA, or total knee joint replacement due to primary OA. All the subjects were unrelated Caucasian females. Their frozen serum samples were retrieved and assessed for targeted metabolite profiling using API4000 Q TRAP LC/MS/MS System (Applied Biosystems, Darmstadt, Germany) equipped with Schimadzu Prominence LC20AD pump and SIL-20AC auto sampler with AbsoluteIDQTM Kit (Biocrates life sciences AG, Austria). Results: A total of 163 serum metabolites were assessed and their concentrations were obtained. The mean of the coefficient of variation (CV) for the 163 metabolites was 0.07±0.05 and 90% of the metabolites had a CV of less than 0.10. The ratios of all pair metabolite concentrations were calculated and tested for the association with knee OA. Overall 14 ratios were significantly associated with knee OA with p ≤ 1.9×10-6 which was the significance level after conservative Bonferroni correction. These ratios were mainly involved in valine and acylcarnitine, namely the ratios of valine to arginine, glutamine, glycine, histidine, tyrosine, and dodecanedioyl-L-carnitine, and the ratios of fumaryl-L-carnitine to propenoyl-L-carnitine, dodecanedioyl-L-carnitine, and lysophosphatidylcholine acyl C26:1. The association between these ratios and knee OA remained strong even after adjustment for age and BMI. Conclusions: This is the first study reporting the identification of novel OA biomarkers using a metabonomics approach. The results suggest that amino acid and acylcarnitine metabolic pathways involving valine and fumaryl-L-carnitine are implicated in the development of OA and have potential clinical use as biomarkers.