Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial medial meniscectomy model of osteoarthritis

Objective: Cathepsin K (cat K), a cysteine protease expressed in osteoclasts, chondrocytes and synovial fibroblasts, degrades several bone and cartilage matrix components suggesting its potential role in osteoarthritis (OA). We investigated the effects of SB-553484, an inhibitor of cat K, on lesion severity and biomarkers of collagen degradation in the canine partial medial meniscectomy model. Methods: A partial medial meniscectomy was performed in mature female beagle dogs. Animals were dosed orally with vehicle or SB-553484 at 50 mg/kg BID for 28 days. The femorotibial joints were evaluated for gross and microscopic histological changes. Biomarkers of collagen degradation were also analyzed. Results: In dogs treated with SB-553484, subjective gross and calculated degeneration scores decreased significantly by 29% and 46%, respectively. Histopathologic evaluation demonstrated that the summed tibial degeneration score decreased significantly by 21%. Inhibition of tibial cartilage degeneration was significant in zone 1 (32%) and the depth ratio of any tibial matrix change was decreased significantly by 28%. Urinary biomarkers of bone and cartilage degradation were also significantly reduced. Conclusion: Treatment with SB-553484 resulted in mild to moderate beneficial effects on gross and histopathological parameters. Reduction of biomarkers of collagen type I and 11 degradation indicated a direct effect of the compound on bone and cartilage. These data suggest that the prevention of cartilage degradation by cat K inhibition may represent a valid strategy for pharmacological intervention in OA and that monitoring collagen degradation biomarkers may provide an indication of the protective effects of inhibition of bone and cartilage degradation. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.