Chondrocyte apoptosis induced by collagen degradation: inhibition by caspase inhibitors and IGF-1.
The main objective of this study was to test the effectiveness of candidate apoptosis inhibitors in limiting chondrocyte apoptosis induced by collagen degradation. Primary human chondrocytes were isolated from normal articular cartilage and grown in monolayer culture. Collagenase was added to the cells in the presence and absence of caspase inhibitors and insulin like growth factor (IGF)-1. The amount of chondrocyte apoptosis was measured using an enzyme linked immunosorbent assay for nucleosomes, a specific and quantitative measure of apoptosis. Chondrocyte apoptosis was induced by collagenase treatment in both a time and dose dependent manner. The non-selective caspase inhibitor Z-VAD, the caspase-3 selective inhibitor Z-DEVD, and the growth factor insulin like growth factor (IGF)-1 inhibited chondrocyte apoptosis induced by collagenase treatment. The caspase-1 selective inhibitor Z-YVAD also blocked chondrocyte apoptosis under these conditions, in contrast to previous studies where caspase-1 inhibition failed to block apoptosis induced by agents such as the topoisomerase inhibitor camptothecin. These data demonstrate that the response of chondrocytes to caspase inhibition may be dependent upon the specific stimulus that initiates apoptosis. Furthermore, these findings suggest that multiple pathways involving both the initiation and execution of programmed cell death are potential targets for chondrocyte apoptosis inhibition therapy.
Lo
Marvin Y
MY
Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA.
Kim
Hubert T
HT
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000201:enzymology; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D017364:Collagenases