Abstract
IntroductionOsteoarthritis (OA) is a common cause of disability in older people, but its aetiology is not yet fully understood. Biomarkers of OA from metabolomics studies have shown potential use in understanding the progression and pathophysiology of OA.ObjectivesTo investigate possible surrogate biomarkers of knee OA in urine using metabolomics to contribute towards a better understanding of OA progression and possible targeted treatment.MethodLiquid chromatography-high resolution mass spectrometry (LC-HRMS) was applied in a case–control approach to explore the possible metabolic differences between the urinary profiles of symptomatic knee OA patients (n = 74) (subclassified into inflammatory OA, n = 22 and non-inflammatory OA, n = 52) and non-OA controls (n = 68). Univariate, multivariate and pathway analyses were performed with a rigorous validation including cross-validation, permutation test, prediction and receiver operating characteristic curve to identify significantly altered metabolites and pathways in OA.ResultsOA datasets generated 7405 variables and multivariate analysis showed clear separation of inflammatory OA, but not non-inflammatory OA, from non-OA controls. Adequate cross-validation (R2Y = 0.874, Q2 = 0.465) was obtained. The prediction model and the ROC curve showed satisfactory results with a sensitivity of 88%, specificity of 71% and accuracy of 77%. 26 metabolites were identified as potential biomarkers of inflammatory OA using HMDB, authentic standards and/or MS/MS database.ConclusionUrinary metabolic profiles were altered in inflammatory knee OA subjects compared to those with non-inflammatory OA and non-OA controls. These altered profiles associated with perturbed activity of the TCA cycle, pyruvate and amino acid metabolism linked to inflammation, oxidative stress and collagen destruction. Of note, 2-keto-glutaramic acid level was > eightfold higher in the inflammatory OA patients compared to non-OA control, signalling a possible perturbation in glutamine metabolism related to OA progression.
Highlights
Osteoarthritis (OA) is a common cause of disability in older people, but its aetiology is not yet fully understood
Chemicals and 171 authentic standards used for the Liquid chromatography-high resolution mass spectrometry (LC-HRMS) optimisation, validation and/or metabolite identification were either HPLC or MS grade; their description and details are summarized in Tables S1 and S2
We cannot definitively ascribe these perturbed metabolites to inflammatory OA changes in the knee joint since they may have a systemic source. Pathway analysis of these metabolites showed that some metabolic pathways were significantly affected in OA participants including pyruvate metabolism, tricarboxylic acid (TCA) cycle and amino acid metabolism (Fig. 4)
Summary
Osteoarthritis (OA) is the most common form of arthritis (Chen et al 2017). The World Health Organisation estimated that 9.6% of men and 18% of women above 60 years of age have symptomatic OA worldwide (WHO, 2020). OA is diagnosed predominantly according to characteristic joint symptoms and abnormal signs, together, if required, with imaging evidence of OA structural changes using radiography (the usual, most widely available modality), ultrasonography (increasingly available but not as comprehensive as MRI in its tissue assessment) or MRI (very sensitive and comprehensive, but costly and least available) (NICE guidelines) (Loeuille, 2012; Menashe et al 2012). These techniques lack the ability to provide pathophysiological information at early stages of OA development. We investigated alterations in urinary metabolic end-products related to perturbations in the metabolic pathways in OA and attempted to relate these changes to biochemical pathways relevant to OA disease and contribute to the understanding of OA progression
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