title: Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis.
abstract: 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.
authors.affiliation: The Scripps Research Institute and the Scripps Clinic, La Jolla, California 92037, USA.
authors.forename: Darryl
authors.initials: D
authors.lastname: D'Lima
authors.forename: Juan
authors.initials: J
authors.lastname: Hermida
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Clifford
authors.initials: C
authors.lastname: Colwell
authors.forename: Martin
authors.initials: M
authors.lastname: Lotz
mesh_terms: 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
chemical_list: 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