The Mast Cell Stabilizer Ketotifen Fumarate Lessens Contracture Severity and Myofibroblast Hyperplasia

Abstract

The propensity of joints to become stiff after trauma is widely appreciated, and the joint capsule is commonly recognized as the major motion-limiting anatomical structure. Affected joint capsules become fibrotic, characterized by myofibroblast and collagen hyperplasia. Mast cell hyperplasia is common within fibrotic tissue, and mast cells are known to synthesize many profibrotic mediators. We hypothesized that mast cell inhibition after skeletal injury would lessen contracture severity and reduce myofibroblast hyperplasia within the joint capsule. Posttraumatic contractures of the knee were created with use of a combination of intra-articular injury and internal immobilization in skeletally mature New Zealand White rabbits. Four groups of animals were studied: a nonoperative control group, a group with the operatively created contracture and no pharmacological treatment (the operative contracture group), and two groups with the operatively created contracture that were treated with a mast cell stabilizer, ketotifen fumarate, at a dose of either 0.5 or 1.0 mg/kg twice daily (the 0.5-mg/kg and 1.0-mg/kg ketotifen groups). After eight weeks of immobilization, flexion contractures were measured and the posterior aspect of the joint capsule was harvested for quantification of myofibroblast and mast cell numbers. Flexion contractures developed in the operative contracture group (mean and standard deviation, 58 degrees +/- 14 degrees ), and the severity of the contractures was reduced in both the group treated with 0.5 mg/kg of ketotifen (42 degrees +/- 17 degrees ) and the group treated with 1.0 mg/kg of ketotifen (45 degrees +/- 10 degrees ) (p < 0.02). The joint capsule myofibroblast and mast cell numbers in the operative contracture group were significantly increased compared with the values in the control group (p < 0.001), and the myofibroblast and mast cell numbers in both ketotifen groups were significantly reduced compared with the values in the operative contracture group (p < 0.001). The use of a mast cell stabilizer, ketotifen, was effective in reducing the biomechanical and cellular manifestations of joint capsule fibrosis in a rabbit model of posttraumatic joint contracture. This finding suggests that an inflammatory pathway, mediated by mast cell activation, is involved in the induction of joint capsule fibrosis after traumatic injury.