title: Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis.
abstract: OBJECTIVE
  To investigate whether alarmins S100A8 and S100A9 are involved in mediating cartilage destruction during murine and human osteoarthritis (OA).
  
  
  METHODS
  Two different murine models of OA that differed in terms of synovial activation were compared. Cartilage destruction was measured histologically. Synovial biopsy and serum samples from OA patients were derived from the Cohort Hip and Cohort Knee (CHECK) patients with symptomatic early OA. Expression of mediators in the synovium was measured by reverse transcription-polymerase chain reaction analysis and immunolocalization.
  
  
  RESULTS
  In collagenase-induced OA, which showed marked synovial activation, interleukin-1β was expressed at significant levels only during the early stages of disease, whereas S100A8 and S100A9 expression remained high for a prolonged period of time (up to day 21 after induction). In S100A9-knockout mice, we found a major impact of S100A8 and S100A9 on synovial activation (62% inhibition) and OA cartilage destruction (45-73% inhibition) as compared to wild-type controls. In contrast, in the surgically induced destabilized medial meniscus model, in which synovial involvement is scant, we found no role of S100A8 and S100A9 in the focal OA cartilage destruction. Examination of arthroscopic synovial biopsy samples from patients in the early symptomatic OA CHECK cohort revealed substantial levels of S100A8 and S100A9 messenger RNA and protein, which correlated significantly with synovial lining thickness, cellularity in the subintima, and joint destruction. Levels of S100A8/A9 serum protein were significantly enhanced (19%) at baseline in patients who had pronounced progression of joint destruction after 2 years.
  
  
  CONCLUSIONS
  Our data suggest that the S100A8 and S100A9 proteins are crucially involved in synovial activation and cartilage destruction during OA and that high levels may predict joint destruction in humans with OA.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. P.vanlent@reuma.umcn.nl
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Arjen B
authors.initials: AB
authors.lastname: Blom
authors.forename: Rik F P
authors.initials: RF
authors.lastname: Schelbergen
authors.forename: Annet
authors.initials: A
authors.lastname: Slöetjes
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Willem F
authors.initials: WF
authors.lastname: Lems
authors.forename: Hans
authors.initials: H
authors.lastname: Cats
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D040501:Calgranulin A / Q000096:biosynthesis* / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011446:Prospective Studies; D013264:Stifle / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D018925:Chemokines; C086145:S100a8 protein, mouse