title: Quantitation OF ARGS aggrecan fragments in synovial fluid, serum and urine from osteoarthritis patients.
abstract: OBJECTIVE
  To characterise ARGS neoepitope concentrations in various matrices from patients with knee osteoarthritis (OA) and assess performance of an immunoassay to facilitate clinical development of therapeutics affecting the A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) pathway.
  
  
  METHODS
  Matched sera, urine, and synovial fluid (SF) (surgical subjects only) were collected from healthy subjects, subjects with knee OA (non-surgical OA), and OA subjects undergoing total knee replacement (OA-TKR; n = 20 per group). Diurnal and inter-day variation was evaluated in the non-surgical OA group over 3 separate visits. Serum and urine samples were collected on two visits for the OA-TKR group with SF taken only at the time of surgery. ARGS neoepitope was quantitated using an optimized immunoassay.
  
  
  RESULTS
  Serum ARGS neoepitope concentrations were elevated in OA-TKR subjects compared to non-surgical OA subjects (P = 0.005) and healthy subjects (P = 0.0002). Creatinine corrected urinary ARGS neoepitope concentrations were more variable, but were also elevated in the OA-TKR subjects compared to healthy subjects (P = 0.008). No significant diurnal effect or inter-day variance was observed in serum or urine. Serum ARGS neoepitope concentrations correlated with age (P = 0.0252) but not with total number of joints with OA involvement. SF ARGS neoepitope concentrations correlated with Western Ontario and MacMaster OA Index (WOMAC) stiffness score (P = 0.04) whereas a weaker, non-significant trend towards positive correlation with combined WOMAC score and the number of concurrent joints was observed.
  
  
  CONCLUSIONS
  This study utilized a sensitive and robust assay to evaluate ARGS neoepitope concentrations in various matrices in OA patients and healthy volunteers. ARGS neoepitope appears promising as a prognostic/stratification marker to facilitate patient selection and as an early pharmacodynamic marker for OA therapeutic trials.
authors.affiliation: GlaxoSmithKline Biopharmaceutical Research & Development, Stevenage, Herts, UK. Electronic address: fiona.m.germaschewski@gsk.com.
authors.forename: F M
authors.initials: FM
authors.lastname: Germaschewski
authors.affiliation: GlaxoSmithKline Research & Development, King of Prussia, PA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Matheny
authors.affiliation: GlaxoSmithKline Research & Development, King of Prussia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Larkin
authors.affiliation: GlaxoSmithKline Research & Development, King of Prussia, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: GlaxoSmithKline Biopharmaceutical Research & Development, Stevenage, Herts, UK.
authors.forename: L R
authors.initials: LR
authors.lastname: Thomas
authors.affiliation: GlaxoSmithKline Research & Development, King of Prussia, PA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Saunders
authors.affiliation: GlaxoSmithKline Biopharmaceutical Research & Development, Stevenage, Herts, UK.
authors.forename: K
authors.initials: K
authors.lastname: Sully
authors.affiliation: Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, Shropshire, UK.
authors.forename: C
authors.initials: C
authors.lastname: Whittall
authors.affiliation: GlaxoSmithKline Clinical Unit, Addenbrookes, Cambridge, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Boyle
authors.affiliation: GlaxoSmithKline Clinical Unit, Addenbrookes, Cambridge, UK.
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.affiliation: Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, Shropshire, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Graham
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry; D000071116:ADAMTS5 Protein; D000368:Aged; D053674:Aggrecans / Q000378:metabolism*; D019645:Arthroplasty, Replacement, Knee; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000502:physiology; D000939:Epitopes / Q000378:metabolism; D005260:Female; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000601:surgery; D010446:Peptide Fragments / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism*
chemical_list: D053674:Aggrecans; D015415:Biomarkers; D000939:Epitopes; D010446:Peptide Fragments; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human
keywords: ARGS; Aggrecan; Biomarker; Immunoassay; Neoepitope; Osteoarthritis