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 (i.a.) 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: I.a. 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.