title: Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis.
abstract: OBJECTIVE
  Alarmins S100A8/A9 regulate pathology in experimental osteoarthritis (OA). Paquinimod is an immunomodulatory compound preventing S100A9 binding to TLR-4. We investigated the effect of paquinimod on experimental OA and human OA synovium.
  
  
  METHODS
  Two OA mouse models differing in level of synovial activation were treated prophylactic with paquinimod. Synovial thickening, osteophyte size and cartilage damage were measured histologically, using an arbitrary score, adapted Pritzker OARSI score or imaging software, respectively. Human OA synovia were stimulated with S100A9, with or without paquinimod.
  
  
  RESULTS
  Paquinimod treatment of collagenase-induced OA (CIOA) resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligaments (67%) and cartilage damage at the medial tibia (47%) and femur (75%; n=7, untreated n=6). In contrast, paquinimod did not reduce osteophyte size and reduced cartilage damage at one location only in destabilised medial meniscus, an OA model with considerably lower synovial activation compared with CIOA. In human OA synovium, paquinimod blocked proinflammatory (interleukin (IL)-6, IL-8, tumour necrosis factor-α) and catabolic (matrix metalloproteinases 1 and 3) factors induced by S100A9 (n=5).
  
  
  CONCLUSIONS
  Prophylactic treatment of paquinimod reduces synovial activation, osteophyte formation and cartilage damage in experimental OA with high synovial activation (CIOA) and ameliorates pathological effects of S100A9 in OA synovium ex vivo.
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: R F
authors.initials: RF
authors.lastname: Schelbergen
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Geven
authors.affiliation: Experimental Rheumatology, 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: Active Biotech AB, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Eriksson
authors.affiliation: Immunology Group, Lund University, Lund, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Leanderson
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: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: F A J
authors.initials: FA
authors.lastname: van de Loo
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M I
authors.initials: MI
authors.lastname: Koenders
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: van der Kraan
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
authors.affiliation: Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Blom
authors.affiliation: Experimental Rheumatology, 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 / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D040502:Calgranulin B / Q000187:drug effects* / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017364:Collagenases / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011804:Quinolines / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D040502:Calgranulin B; D007166:Immunosuppressive Agents; D011804:Quinolines; C576329:S100A9 protein, mouse; D017364:Collagenases; C573440:paquinimod
keywords: Inflammation; Osteoarthritis; Synovitis