title: Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis.
abstract: OBJECTIVE
  Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA.
  
  
  METHODS
  OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years.
  
  
  RESULTS
  Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline.
  
  
  CONCLUSIONS
  S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R F P
authors.initials: RF
authors.lastname: Schelbergen
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: de Munter
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M H J
authors.initials: MH
authors.lastname: van den Bosch
authors.affiliation: Departments of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: F P J G
authors.initials: FP
authors.lastname: Lafeber
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Sloetjes
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Institute of Immunology, University of Muenster, Muenster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Blom
authors.affiliation: Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: P L E M
authors.initials: PL
authors.lastname: van Lent
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D040501:Calgranulin A / Q000172:deficiency / Q000502:physiology*; D040502:Calgranulin B / Q000502:physiology*; D002358:Cartilage, Articular / Q000201:enzymology / Q000503:physiopathology; D020219:Chondrogenesis / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010003:Osteoarthritis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D054850:Osteophyte / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D015415:Biomarkers; D040501:Calgranulin A; D040502:Calgranulin B; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D020782:Matrix Metalloproteinases
keywords: Chondrocytes; Cytokines; Osteoarthritis; Synovitis