Oral Presentation Matrix Biology Society of Australia and New Zealand Annual Meeting 2012

Protease Activated Receptor-2 (PAR-2), but not PAR-1, modulates synovial macrophage maturation in post-traumatic osteoarthritis.  (#31)

Miriam T Jackson 1 , Babak Moradi 2 , Susan Smith 1 , Christopher Jackson 1 , Christopher B Little 1
  1. Kolling Institute of Medical Research, St Leonards, NSW, Australia
  2. Orthopaedic Clinic, University of Heidelberg, Heidelberg, Germany

Introduction: Osteoarthritis (OA) is a disease of the entire joint and although commonly considered non-inflammatory, synovitis is present. Whether synovitis occurs secondary to cartilage breakdown or is a primary initiator is unclear. Mice deficient in protease activated receptor (PAR)-1 and PAR-2 have early chondroprotection in a model of post-traumatic (ptOA). We hypothesise this could be associated with a reduction in post-surgical inflammation. The purpose of this current study is to determine the effect of PAR-1andPAR-2 on ptOA-associated inflammation.

Methods: ptOA was induced in WT, PAR-1-/- and PAR-2-/- mice using DMM. Synovial inflammation scored histologically at 4 & 8 weeks post-surgery. Synovial and remaining joint tissues (bone/cartilage) were isolated from additional mice harvested 1-week post-surgery. Gene expression of inflammatory cytokines and cell subtypes in synovial and bone/cartilage samples were examined. Immune cells were isolated from synovial tissues and quantified by flow cytometry.

Results: Synovial inflammation was significantly reduced in PAR-2-/-, but not PAR-1-/-, mice at 4 and 8 weeks. Increased expression of inflammatory cytokines and cell markers was observed in the synovial tissue after surgery in all genotypes. Post-operative cellular influx was reduced in the synovial tissue of PAR-1-/- and PAR-2-/- mice in comparison to WT. When analysed further for the activation and maturation status of the CD11b+ mononuclear cells we detected a significant reduction of CD11b+F4/80+Ly6clow mature macrophages in PAR-2-/- but not PAR-1-/-.

Discussion: Inhibition of DMM-induced cartilage damage in PAR-2-/- mice was due to reduced post-surgical inflammation. Inflammatory and destructive responses in OA synovium are dependent largely on macrophages. Our data shows that PAR-2-/- synovium has fewer mature macrophages and less structural cartilage damage, suggesting PAR-2, but not PAR-1, has a pro-inflammatory role in OA. Depleting synovial macrophages early after joint injury may be a novel treatment to reduce the onset of ptOA.