title: Metabolomic analysis of human plasma reveals that arginine is depleted in knee osteoarthritis patients.
abstract: OBJECTIVE
  To identify novel biomarker(s) for knee osteoarthritis (OA) using a metabolomics approach.
  
  
  METHODS
  We utilized a two-stage case-control study design. Plasma samples were collected from knee OA patients and healthy controls after 8-h fasting and metabolically profiled using a targeted metabolomics assay kit. Linear regression was used to identify novel metabolic markers for OA. Receiver operating characteristic (ROC) analysis was used to examine diagnostic values. Gene expression analysis was performed on human cartilage to explore the potential mechanism for the novel OA marker(s).
  
  
  RESULTS
  Sixty-four knee OA patients and 45 controls were included in the discovery stage and 72 knee OA patients and 76 age and sex matched controls were included in the validation stage. We identified and confirmed six metabolites that were significantly associated with knee OA, of which arginine was the most significant metabolite (P < 3.5 × 10(-13)) with knee OA patients having on average 69 μM lower than that in controls. ROC analysis showed that arginine had the greatest diagnostic value with area under the curve (AUC) of 0.984. The optimal cutoff of arginine concentration was 57 μM with 98.3% sensitivity and 89% specificity. The depletion of arginine in OA patients was most likely due to the over activity of arginine to ornithine pathway, leading to imbalance between cartilage repair and degradation.
  
  
  CONCLUSIONS
  Arginine is significantly depleted in refractory knee OA patients. Further studies within a longitudinal setting are required to examine whether arginine can predict early OA changes.
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Likhodii
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Aref-Eshghi
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: P E
authors.initials: PE
authors.lastname: Harper
authors.affiliation: Department of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Martin
authors.affiliation: Department of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Furey
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Green
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Randell
authors.affiliation: Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Rahman
authors.affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada; Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. Electronic address: guangju.zhai@med.mun.ca.
authors.forename: G
authors.initials: G
authors.lastname: Zhai
mesh_terms: D000368:Aged; D001120:Arginine / Q000097:blood* / Q000172:deficiency; D019645:Arthroplasty, Replacement, Knee; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000097:blood* / Q000175:diagnosis / Q000601:surgery; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D001120:Arginine
keywords: Arginine; Knee osteoarthritis; Metabolomics