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.


CONCLUSIONS
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.
D'Lima
Darryl
D
The Scripps Research Institute and the Scripps Clinic, La Jolla, California 92037, USA.
Hermida
Juan
J
Hashimoto
Sanshiro
S
Colwell
Clifford
C
Lotz
Martin
M
D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis; D016923:Cell Death; D019902:Chondrocytes / Q000737:chemistry; D007150:Immunohistochemistry; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011817:Rabbits
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases