title: Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis.
abstract: OBJECTIVE
  To evaluate the role of three cartilage-derived biomarkers on osteoarthritis (OA): urinary C-terminal telopeptide (uCTX-II), serum cartilage oligomeric protein (sCOMP), and serum MMP degraded type II collagen (sC2M).
  
  
  METHODS
  Samples from 3582 individuals from the Rotterdam Study, the Genetics osteoArthritis and Progression (GARP), the Chingford Study and the TwinsUK cohort were assayed using enzyme-linked immune sorbent assays. Log10 of concentration levels were correlated with risk of hip, hand and knee OA, hip and knee OA severity and incidence, and progression of knee OA, adjusting for age, gender and body mass index (BMI). Results were meta-analysed to assess overall significance.
  
  
  RESULTS
  After adjusting for covariates, sCOMP was associated with knee OA and hip and knee OA incidence. Furthermore, sC2M was associated with knee OA incidence and progression. After adjustment for multiple tests (Bonferroni P < 0.002) only the association between sCOMP and knee OA remained significant (odds ratio (OR) = 3.26 (95%CI 1.63-10.1) P = 0.0008 for each standard deviation (SD) increase in biomarker levels). Levels of uCTX-II were significantly associated with risk of hand, hip and knee OA, progression and incidence of knee OA. A receiver operating characteristics (ROC) analysis showed a consistent improvement in prediction of knee OA progression from an average area under the curve (AUC) is 0.646 for age, sex and BMI alone to an AUC = 0.668 including uCTX-II for prediction.
  
  
  CONCLUSIONS
  uCTX-II is the most informative biochemical marker for prediction of OA. Both sCOMP and C2M showed some association with OA, thus indicating that they are descriptive of disease activity.
authors.affiliation: Academic Rheumatology, University of Nottingham, Clinical Sciences Bld, Nottingham City Hospital, Nottingham NG5 1PB, UK; Dept of Twin Research, King's College London, London SE1 7EH, UK. Electronic address: ana.valdes@kcl.ac.uk.
authors.forename: A M
authors.initials: AM
authors.lastname: Valdes
authors.affiliation: Dept of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Meulenbelt
authors.affiliation: Synarc Laboratory, Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Chassaing
authors.affiliation: NIHR Musculoskeletal Biomedical Research Unit and ARUK Centre of Excellence for Sport, Exercise and Osteoarthritis University of Oxford, UK.
authors.forename: N K
authors.initials: NK
authors.lastname: Arden
authors.affiliation: Dept of General Practice and Dept of Orthopaedics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Bierma-Zeinstra
authors.affiliation: Dept of Twin Research, King's College London, London SE1 7EH, UK.
authors.forename: D
authors.initials: D
authors.lastname: Hart
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Rheumatology, Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Karsdal
authors.affiliation: Dept of Rheumatology and Dept of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Kloppenburg
authors.affiliation: Dept of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Kroon
authors.affiliation: Dept of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: E P
authors.initials: EP
authors.lastname: Slagboom
authors.affiliation: Dept of Twin Research, King's College London, London SE1 7EH, UK.
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands; Dept of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Dept of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: J B
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Rheumatology, Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
authors.forename: A C
authors.initials: AC
authors.lastname: Bay-Jensen
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000652:urine; D064236:Cartilage Oligomeric Matrix Protein / Q000097:blood; D024043:Collagen Type II / Q000097:blood* / Q000652:urine; D018450:Disease Progression; D006801:Humans; D015994:Incidence; D020782:Matrix Metalloproteinases / Q000502:physiology; D010003:Osteoarthritis / Q000175:diagnosis* / Q000453:epidemiology / Q000378:metabolism; D010446:Peptide Fragments / Q000652:urine*; D015995:Prevalence
chemical_list: D015415:Biomarkers; D064236:Cartilage Oligomeric Matrix Protein; D024043:Collagen Type II; D020782:Matrix Metalloproteinases; D010446:Peptide Fragments; C000590554:C-terminal cross-linking telopeptide of type II collagen, human; C577553:TSP5 protein, human
keywords: Biochemical markers; Cartilage; Osteoarthritis progression; Receiver operating characteristics curve