Antiplasmin, but not amiloride, prevents synovitis and cartilage damage following hemarthrosis in hemophilic mice

Abstract

Blood-induced joint damage is characterized by synovitis and cartilage damage. Recently, we demonstrated that joint bleeding in hemophilic mice results in elevated synovial levels of urokinase plasminogen activator (u-PA) and plasmin, and in plasmin-mediated cartilage damage. To evaluate whether treatment with amiloride (an inhibitor of u-PA) or antiplasmin attenuates synovitis and cartilage damage following joint bleeding in hemophilic mice. Following the induction of joint bleeding, hemophilic mice were randomized between daily oral treatment with amiloride (1 mg kg⁻¹) or control, or weekly intra-articular treatment with amiloride (2.5 mg mL⁻¹), antiplasmin (2.5 mg mL⁻¹), or control. After 5 weeks of treatment, synovitis and cartilage damage were determined on hematoxylin and eosin-stained (Valentino score) and Safranin O-stained sections, respectively. No effects of oral and intra-articular treatment with amiloride were found. In contrast, intra-articular treatment with antiplasmin resulted in significant (P < 0.01) reductions in both synovitis (score 1, 11.1% vs. 0%; score 2, 11.1% vs. 4.2%; score 3, 61.1% vs. 16.7%; score 4, 5.6% vs. 29.2%; score 5, 11.1% vs. 20.8%; score 6, 7.7% vs. 8.3%; score 7, 0% vs. 8.3%; and score 8, 0% vs. 12.5%) and cartilage damage (score 2, 10% vs. 8.3%; score 3, 50% vs. 12.5%; score 4, 30% vs. 33.3%; score 5, 10% vs. 33.3%; and score 6, 0% vs. 16.7%) as compared with controls. Intra-articular treatment with antiplasmin (but not amiloride) following joint bleeding prevented synovitis and cartilage damage in hemophilic mice. These data offer promise for the use of antiplasmin as a new therapeutic intervention for patients who suffer from joint bleeds despite administration of clotting factor.