Abstract & Commentary
Synopsis: In both in vitro and in vivo trials, the number of apoptotic cells increased significantly in response to mechanical loading. Furthermore, caspase inhibitors reduced chondrocyte apoptosis following mechanical injury.
Source: D’Lima DD, et al. Impact of mechanical trauma on matrix and cells. Clin Orthop Relat Res. 2002;391:S90-S99.
It has been suggested that chondrocyte death may be a critical factor in the response of cartilage to injury. Although articular cartilage responds differently to different types of mechanical stimuli, the contribution of cell death to matrix degradation has not been fully characterized. The present study sought to determine the effect of mechanical injury on chondrocyte viability and matrix degradation.
Both in vivo and in vitro effects of mechanical loading on cartilage were examined. The models of mechanical injury investigated were transient static compression, impact loading, and creation of a cartilage defect in articular cartilage. The release of glycosaminoglycan (GAG) and percentage of apoptotic cells were measured to determine the response to the mechanical loading. The inhibition of chondrocyte apoptosis by a pan-caspase inhibitor, z-VAD-fmk, in human articular cartilage explants was also determined.
The bovine and human cartilage explants were mechanically loaded by an Instron 8511 servohydraulic testing machine (Instron Corporation, Boston, Mass). The simulation of acute joint injury followed either a dose response model (low, moderate, high) or a repetitive model where following a small preload, a 30% strain was applied to the explants at a rate of 3/sec lasting for 500 ms. To stimulate traumatic injury, 3-mm drill holes in weightbearing portions of bovine femoral condyles and human talar domes were created (no penetration of subchondral bone), and 5 mm disks from around the drill holes were harvested. Additionally, unilateral patellas in eight anesthetized rabbits were subjected to an impact load by dropping a 3 kg weight from a height of 100 cm.
For the dose-response experiments, it was determined that GAG release increased with the intensity of the loading at 48 hours after loading. The moderate load and high load groups showed significantly higher apoptosis rates than the control groups. A correlation of GAG release with apoptosis rate was observed (r = 0.67; P = 0.02). For the repetitive injury model, explants subjected to 30% strain had a mean apoptosis rate of 34% (± 12) compared to those cultured in the presence of caspase inhibitor which exhibited a mean apoptosis rate of 21% (± 11) with a significant reduction in GAG release.
All bovine cartilage explants with drill holes showed a higher rate of apoptosis along the margin of the drill holes (55.2% ± 30.2) as compared to the sharply punched out margins of the disks (26.8% ± 8.6; P = 0.02). In vivo impact loading of patellar cartilage demonstrated 15% apoptosis compared to 1% in the unimpacted cartilage (P < 0.01).
Comment by Brian J. Cole, MD, MBA
The present study has shown that chondrocyte apoptosis can be induced both in vitro and in vivo proportional to the level of mechanical loading and injury. However, the level of apoptosis following injury in vivo is much lower than that found in vitro. The findings from this study also indicate that, in vitro, apoptosis induced by mechanical loading can be reduced through the use of caspase inhibitors. These results should be considered when clinicians harvest the patellar bone block during ACL reconstruction, harvest and handle chondrocytes for cell transplantation, and harvest or impact osteochondral grafts. Clearly, our current techniques must minimize the chance for iatrogenic injury. Additionally, our postoperative rehabilitation protocols may benefit from considering this data. Additional research focused on maturing tissue (ie, fibrocartilage, hyaline like cartilage, integration of osteochondral grafts) may help to fine tune our rehabilitation protocols. In order to determine the clinical efficacy of caspase inhibitors in patients exposed to surgical trauma of cartilage, further in vivo studies are required.
Dr. Cole, Assistant Professor, Orthopaedic Surgery, Rush Presbyterian Medical Center, Midwest Orthopaedics, Chicago, IL, is Associate Editor of Sports Medicine Reports.
Author Acknowledgment: The author of this review would like to thank Nina Shervin, BA for her help in preparing the manuscript.
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