Preventing chondrocyte programmed cell death caused by iatrogenic injury.
Cartilage repair technology is advancing at a rapid pace. However, all techniques share a common weakness-unintentional chondrocyte cell death resulting from cartilage injury that occurs during preparation of the defect site. The loss of chondrocytes at the edge of host cartilage is likely to contribute to failed integration of regenerated tissue or grafts to the surrounding cartilage. Recent studies have demonstrated that "apoptosis", or programmed cell death (PCD), may be responsible for much of the cell death caused by cartilage injury. Theoretically, inhibitors of key pathways responsible for PCD could rescue chondrocytes and improve the results of cartilage repair surgery. The purpose of this study was to test the hypothesis that short-term, intra-articular PCD inhibitor treatment can limit chondrocyte death in vivo following simulated preparation of host cartilage for a repair procedure. A microcurette was used to create full-thickness articular cartilage injuries to the femoral condyles of adult New Zealand White rabbits. Animals received daily intra-articular injections either with a potent PCD inhibitor or with vehicle alone. Treatment with the inhibitor resulted in a significant reduction in the percentage of chondrocytes undergoing PCD compared to controls [treated=10.1+/-2.4%; controls=26.5+/-3.6%; (p=0.0013)]. These results provide proof of concept for the use of PCD inhibitors to enhance the results of cartilage repair surgeries.
Costouros
John G
JG
Department of Orthopaedic Surgery, University of California Medical Center, San Francisco, CA 95119, United States. costouros@yahoo.com
Kim
Hubert T
HT
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002358:Cartilage, Articular / Q000293:injuries* / Q000473:pathology; D061945:Caspase Inhibitors; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D007049:Iatrogenic Disease; D020287:In Situ Nick-End Labeling; D007270:Injections, Intra-Articular; D023421:Models, Animal; D011817:Rabbits
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone