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The Mast Cell Stabilizer Ketotifen Fumarate Lessens Contracture Severity and Myofibroblast HyperplasiaA Study of a Rabbit Model of Posttraumatic Joint Contractures
Michael J. Monument, MD1; David A. Hart, PhD1; A. Dean Befus, PhD2; Paul T. Salo, MD1; Mei Zhang, MD1; Kevin A. Hildebrand, MD1
1 Division of Orthopaedic Surgery, McCaig Institute for Bone and Joint Health, Faculty of Medicine, University of Calgary, G207 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada. E-mail address for M.J. Monument: mjmonume@ucalgary.ca. E-mail address for K.A. Hildebrand: hildebrk@ucalgary.ca
2 Pulmonary Research Group, Department of Medicine, Room 5504-HMRC (Heritage Medical Research Centre), University of Alberta, Edmonton, AB T6G 2S2, Canada
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from the Canadian Orthopaedic Foundation "Robert Salter Award" 2007-2008. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at the Division of Orthopaedic Surgery, McCaig Institute for Bone and Joint Health, Calgary, Alberta, Canada

Copyright ©2010 American Society for Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2010 Jun 01;92(6):1468-1477. doi: 10.2106/JBJS.I.00684
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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° ± 14°), and the severity of the contractures was reduced in both the group treated with 0.5 mg/kg of ketotifen (42° ± 17°) and the group treated with 1.0 mg/kg of ketotifen (45° ± 10°) (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.

Clinical Relevance: 

These results suggest that mast cell activation is an important event in the genesis of posttraumatic joint contractures. Additional work is needed to determine if mast cell inhibition has a role in the prevention of posttraumatic joint contractures in humans.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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