Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis

Objective. To examine the therapeutic efficacy of caspase inhibitors in experimental osteoarthritis (OA). Methods. Experimental OA was induced in rabbits by anterior cruciate ligament transection (ACLT). Rabbits were treated with intraarticular (IA) injections of caspase inhibitors 3 times per week starting 1 week postoperatively. Animals were killed 9 weeks after ACLT, for macroscopic, histologic, and immunohistochemical assessment of the knee joints. Results. IA administration of the pan-caspase inhibitor Z-VAD-FMK significantly reduced cartilage degradation, as assessed by macroscopic and microscopic criteria. Untreated knees showed large numbers of chondrocytes with active caspase 3 and the p85 fragment of poly(ADP-ribose) polymerase (PARP p85) that is generated during apoptosis. The frequency of cells positive for PARP p85 and active caspase 3 was reduced in Z-VAD-FMK-treated knees. Inhibitors specific for caspase 3 or caspase 8 showed no significant efficacy. Caspase 1 inhibitor and the combination of caspase 3 and caspase 8 inhibitors reduced OA pathology. Conclusion. These results provide direct support for a role of cell death in OA pathogenesis. Caspase inhibitors reduced the severity of cartilage lesions in experimental OA, suggesting that they may have disease-modifying activity in human OA.