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Prophylactic treatment with S100A9 inhibitor paquinimod reduces pathology in experimental collagenase-induced osteoarthritis
  1. R F Schelbergen1,
  2. E J Geven1,
  3. M H J van den Bosch1,
  4. H Eriksson2,
  5. T Leanderson3,
  6. T Vogl4,
  7. J Roth4,
  8. F A J van de Loo1,
  9. M I Koenders1,
  10. P M van der Kraan1,
  11. W B van den Berg1,
  12. A B Blom1,
  13. P L E M van Lent1
  1. 1Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Active Biotech AB, Lund, Sweden
  3. 3Immunology Group, Lund University, Lund, Sweden
  4. 4Institute of Immunology, University of Muenster, Muenster, Germany
  1. Correspondence to Dr Peter LEM van Lent, Experimental Rheumatology, Department of Rheumatology, Radboud University Medical Center, Geert Grooteplein 28, PO Box 9101, Nijmegen 6500 HB, The Netherlands; Peter.vanLent{at}radboudumc.nl

Abstract

Objectives 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.

Materials and 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.

  • Osteoarthritis
  • Inflammation
  • Synovitis

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