Silencing of protease‐activated receptors attenuates synovitis and cartilage damage following a joint bleed in haemophilic mice

Introduction and aim Joint bleeding results in blood‐induced arthropathy. We investigate whether a joint bleed alters protease‐activated receptor ( PAR ) expression, and whether treatment with small interfering RNA (siRNA) targeted against PAR 1–4 attenuates synovitis and cartilage damage. Methods Protease‐activated receptor expression was evaluated upon a joint bleed in haemophilic mice and in humans. In addition, mice with a joint bleed were randomized between treatment with PAR 1–4 siRNA or control and evaluated for the presence of synovitis and cartilage damage. Also, human cartilage was transfected with PAR 1–4 siRNA or control, and evaluated for plasmin‐induced cartilage damage. Results Following a joint bleed, we observed an increase in synovial PAR 1, ‐2 and ‐4 expression, and an increase in chondrocyte PAR 2 and ‐3 expression in mice (all P < 0.05). Also an increase in synovial PAR 1 and chondrocyte PAR 4 expression in patients was observed (both P < 0.05). Treatment of a joint bleed in haemophilic mice with PAR 1–4 siRNA attenuates synovitis and cartilage damage (both P < 0.01). Treatment of human cartilage tissue explants with PAR 1–4 siRNA reduced plasmin‐induced cartilage damage ( P < 0.01). Conclusion This study demonstrates that synovial and chondrocyte PAR expression is altered upon a joint bleed, and that treatment with PAR 1–4 siRNA attenuates synovitis and plasmin‐induced cartilage damage.