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Licofelone Reduces Progression of Structural Changes in a Canine Model of Osteoarthritis Under Curative Conditions: Effect on Protease Expression and Activity
MAXIM MOREAU, CHRISTELLE BOILEAU, JOHANNE MARTEL-PELLETIER, JULIE BRUNET, STEFAN LAUFER, and JEAN-PIERRE PELLETIER ABSTRACT. Objective. We investigated the effectiveness of licofelone, a combined 5-lipoxygenase and cyclooxygenase inhibitor, on structural changes in the anterior cruciate ligament (ACL) experimental dog model of osteoarthritis (OA) under therapeutic conditions. The effect of drug treatment on the expression and activity of metalloproteases in the OA cartilage was also studied. Methods. The cranial cruciate ligament of the right stifle joint was surgically sectioned in 14 dogs to create OA lesions. Of these dogs, 7 received placebo treatment and served as OA controls, while 7 were treated with licofelone 2.5 mg/kg twice daily for an 8-week period, starting 4 weeks after surgery. At necropsy, macroscopic evaluations were made of the size of osteophytes and the severity of cartilage lesions on femoral condyles and tibial plateaus. Collagenase and other metalloprotease activity levels in cartilage were measured. Levels of gene expression of matrix metalloprotease (MMP-1), MMP-13, cathepsin K, and ADAMTS-5 were quantified by RT-PCR. Results. Licofelone treatment reduced the development of osteophytes and size of cartilage lesions on the femoral condyles and on the tibial plateaus (p < 0.04). Drug treatment also significantly decreased collagenase (p < 0.02) and metalloprotease (p < 0.04) activities, as well as the levels of gene expression of MMP-1 (p < 0.01), MMP-13 (p < 0.05), cathepsin K, and ADAMTS-5 (p = 0.01). Conclusion. Under therapeutic conditions licofelone showed the ability to reduce the progression of structural changes in experimental dog OA. This beneficial effect is likely mediated through decrease in the synthesis of a number of catabolic factors, including proteolytic enzymes, involved in cartilage breakdown. (First Release May 1, 2006; J Rheumatol 2006;33:1176–82) Key Indexing Terms:
LICOFELONE
From the Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, Montreal, Quebec, Canada. Supported by an unrestricted grant from Merckle GmbH, Ulm, Germany. M. Moreau, MSc, The Companion Animal Research Group, Faculty of Veterinary Medicine, University of Montreal, St. Hyacinthe, Quebec; C. Boileau, PhD, Postdoctoral Fellow; J. Martel-Pelletier, PhD, Professor of Medicine, Director, Osteoarthritis Research Unit; J. Brunet, PhD, Research Associate, Osteoarthritis Research Unit; S. Laufer, PhD, Head, Department of Pharmaceutical Chemistry/Medicinal Chemistry, Eberhard-Karls-University, Tübingen Institute of Pharmacy, Tübingen, Germany; J-P. Pelletier, MD, Professor of Medicine, Director, Osteoarthritis Research Unit, University of Montreal Hospital Centre. Address reprint requests to Dr. J-P. Pelletier, Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, 1560 Sherbrooke St. East, Montreal, Quebec H2L 4M1, Canada. E-mail: dr@jppelletier.ca Accepted for publication January 27, 2006.
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