Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury.
OBJECTIVE
Recent studies have demonstrated that articular cartilage injury leads to chondrocyte death through a mechanism termed "apoptosis", or programmed cell death (PCD). Inhibitors of caspases, key enzymatic mediators of apoptosis, have been shown to block chondrocyte PCD. We hypothesized that short-term intra-articular administration of a potent caspase inhibitor would decrease chondrocyte PCD and subsequent cartilage degeneration following experimental osteochondral injury in rabbits.


METHODS
Adult New Zealand white rabbits were subjected to osteochondral injuries of their femoral condyles. Knees in the treatment group received daily intra-articular injections of the broad-spectrum caspase inhibitor Z-VAD-fmk for 7 days, while the control group received injections of vehicle alone. Seven days postinjury, one group of rabbits was sacrificed to assess levels of chondrocyte PCD. A second group was sacrificed 42 days postinjury for histological evaluation to measure cartilage degeneration and cartilage repair.


RESULTS
Seven days postinjury, there was a 45% reduction in chondrocyte PCD in the caspase inhibitor treated knees as compared to controls (P=0.01). Forty-two days postinjury, treated knees were found to have 17.9% greater chondrocyte survival (P<0.01) and 7.6% greater articular cartilage thickness (P=0.01).


CONCLUSIONS
Intra-articular administration of the caspase inhibitor Z-VAD-fmk effectively blocks chondrocyte PCD following experimental osteochondral injury in this model. Inhibition of chondrocyte PCD rescues chondrocytes that would otherwise die, limiting subsequent cartilage loss. To our knowledge, this study is the first to demonstrate that short-term inhibition of chondrocyte PCD leads to long-term preservation of cartilage in vivo.
Department of Orthopaedic Surgery, University of California, San Francisco, 500 Parnassus, Avenue Box 0728, San Francisco, CA 94143-0728, USA.
A C
AC
Dang
A P
AP
Warren
H T
HT
Kim
D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D061945:Caspase Inhibitors; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005269:Femur; D007270:Injections, Intra-Articular; D011817:Rabbits
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone