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Scientific Article   |    
Cartilage Injury Induces Chondrocyte Apoptosis
Darryl D. D'Lima, MD; Sanshiro Hashimoto, MD; Peter C. Chen, PhD; Martin K. Lotz, MD; Clifford W. ColwellJr., MD
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Darryl D. D’Lima, MD
Peter C. Chen, PhD
Clifford W. Colwell Jr., MD
Division of Orthopaedic Surgery, Scripps Clinic, MS126, 11025 North Torrey Pines Road, Suite 140, La Jolla, CA 92037. E-mail address for D.D. D’Lima: ddlima@scripps.edu. E-mail address for C.W. Colwell Jr.: colwell@scripps.edu

Sanshiro Hashimoto, MD
Martin K. Lotz, MD
Division of Arthritis Research, The Scripps Research Institute, MEM 161, 10550 North Torrey Pines Road, La Jolla, CA 92037

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Orthopaedic Research and Education Foundation Grant 98-052, National Institutes of Health Grant AG07996, the ALSAM Foundation, and the Skaggs Institute for Research. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

The Journal of Bone & Joint Surgery.  2001; 83:S19-21 
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Cartilage injury is one of the more important factors leading to secondary osteoarthritis. Previous histologic studies have demonstrated loss of chondrocyte viability after mechanical injury. More recently, it has been shown that chondrocytes undergo apoptosis in response to wounding or injurious compression1,2. An in vitro model was therefore developed to determine the effect of mechanical injury on chondrocyte viability and matrix degradation and whether cell death occurs as apoptosis or necrosis.
 
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+Fig. 1-A:Figs. 1-A and 1-B TUNEL staining demonstrating apoptotic cells. The apoptotic cells are seen as bright green fluorescence, and the normal cells are demonstrated by orange counterstain (original magnification, 100). Fig. 1-A Control explant demonstrating minimal apoptosis.
 
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+Fig. 1-B:Figs. 1-A and 1-B TUNEL staining demonstrating apoptotic cells. The apoptotic cells are seen as bright green fluorescence, and the normal cells are demonstrated by orange counterstain (original magnification, 100). Fig. 1-B Loaded explant demonstrating a high rate of apoptosis.
 
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+Fig. 2-A:Figs. 2-A and 2-B Electron microscopy demonstrating apoptotic cells. N = nucleus and Cy = cytoplasm (original magnification, 4700). Fig. 2-A Normal chondrocytes from a control explant.
 
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+Fig. 2-B:Figs. 2-A and 2-B Electron microscopy demonstrating apoptotic cells. N = nucleus and Cy = cytoplasm (original magnification, 4700). Fig. 2-B Apoptotic chondrocytes from a high-load explant. Note the shrinkage of the nucleus and the apoptotic cells and the presence of matrix vesicles (MV).
 
 
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+Fig. 4:Dose response. Explants were loaded at the intensities indicated. The number of cells demonstrating apoptosis compared with all visible cells was expressed as a percentage. Glycosaminoglycan (GAG) levels in the media were measured and expressed as a percentage of explant glycosaminoglycan content.
 
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+Fig. 5:Time-course of apoptosis. Explants were loaded at 30% strain for 500 msec and harvested at various time-points up to ninety-six hours. Apoptosis was measured as the percentage of cells staining positive.
In the first set of experiments, sixty-four full-thickness cartilage explants, 5 mm in diameter, were harvested from the weight-bearing regions of the medial femoral condyles of four fresh bovine knee joints with use of a dermal punch. Explants were cultured for forty-eight hours in Dulbecco modified Eagle medium supplemented with 10% fetal bovine serum. These explants were divided into four groups: control, low load, moderate load, and high load. Low-load explants were subjected to a single static radially unconfined stress of 7 MPa; moderate-load explants, to 14 MPa; and high-load explants, to 23 MPa. The duration of loading was 500 msec. The control-group explants were not loaded. At forty-eight hours after injury, glycosaminoglycan levels were measured in the media with use of dimethylene blue assay. Apoptotic cells were counted with use of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). Apoptosis was confirmed by electron microscopy in selected samples.
In the second set of experiments, human cartilage explants were taken from the femoral and tibial condyles and talar domes of macroscopically normal fresh cadaver joints. These were divided into two groups: loaded (subjected to 30% strain for 500 msec) and control (unloaded). Apoptosis levels were measured at forty-eight hours.
In the third set of experiments, tibial cartilage explants were loaded at 30% strain for 500 msec, and apoptosis levels were measured at zero, three, six, twenty-four, forty-eight, and ninety-six hours after loading.
Loaded cartilage demonstrated higher percentages of apoptotic cells when compared with control cartilage (Figs. 1-A, 1-B, 2-A, and 2-B). The mean percentages of apoptotic cells in the different groups are detailed in Figure 3.
Dose response: The mean differences in glycosaminoglycan levels and apoptosis rates between control and experimental explants were significant at moderate and high loads (p < 0.01). Both glycosaminoglycan levels and apoptosis rates demonstrated a dose response with loading magnitudes (Fig. 4). The percentage of cells demonstrating apoptosis was related to load intensity and was associated with the levels of glycosaminoglycan in the media (p < 0.05).
Human cartilage: Cartilage from different locations from human donors also demonstrated apoptosis in response to mechanical injury (p < 0.05). The time-course study demonstrated that apoptotic counts do not change much in the first three hours after injury (Fig. 5). Beginning at six hours, there was a consistent increase in apoptosis levels until ninety-six hours after injury.
The results of this study demonstrated that mechanical injury consistently induces chondrocyte death in the form of apoptosis. The first set of studies, using bovine cartilage, demonstrated a dose response, with glycosaminoglycan release and apoptosis rates increasing with increased injury levels. An increase in the percentage of apoptotic cells was also seen in human knee and talar cartilage, demonstrating that cartilage from a variety of sources displays a similar response to mechanical injury. This loss of cell viability is accompanied by an increase in the levels of glycosaminoglycan in the culture media, suggesting matrix degradation. The results of the time-course study demonstrated a progressive increase in the levels of apoptotic cells after injury, offering a potentially therapeutic window. Data presented in another report3 demonstrated that apoptosis can be inhibited, suggesting a potential for pharmacologic modulation of the effects of cartilage injury.
TewSR, Kwan AP, Hann A, Thompson BM,Archer CW. The reactions of articular cartilage to experimental wounding: role of apoptosis. Arthritis Rheum,2000;41: 215-25. 41215  2000 
 
LoeningAM, James IE, Levenston ME, Badger AM, Frank EH, Kurz B, Nuttall ME, Hung HH, Blake SM, Grodzinsky AJ,Lark MW. Injurious mechanical compression of bovine articular cartilage induces chondrocyte apoptosis. Arch Biochem Biophys,2000;381: 205-12. 381205  2000  [PubMed]
 
D’Lima DD, Hashimoto S, Chen PC, Lotz MK,Colwell CW Jr. Prevention of chondrocyte apoptosisJ Bone Joint Surg Am200183(Suppl 2)25-26. J Bone Joint Surg Am,200183(Suppl 2)25-26;83(Suppl 2): 25-26. 83(Suppl 2)25  200183(Suppl 2)25-26 
 

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Anchor for JumpAnchor for Jump
+Fig. 1-A:Figs. 1-A and 1-B TUNEL staining demonstrating apoptotic cells. The apoptotic cells are seen as bright green fluorescence, and the normal cells are demonstrated by orange counterstain (original magnification, 100). Fig. 1-A Control explant demonstrating minimal apoptosis.
Anchor for JumpAnchor for Jump
+Fig. 1-B:Figs. 1-A and 1-B TUNEL staining demonstrating apoptotic cells. The apoptotic cells are seen as bright green fluorescence, and the normal cells are demonstrated by orange counterstain (original magnification, 100). Fig. 1-B Loaded explant demonstrating a high rate of apoptosis.
Anchor for JumpAnchor for Jump
+Fig. 2-A:Figs. 2-A and 2-B Electron microscopy demonstrating apoptotic cells. N = nucleus and Cy = cytoplasm (original magnification, 4700). Fig. 2-A Normal chondrocytes from a control explant.
Anchor for JumpAnchor for Jump
+Fig. 2-B:Figs. 2-A and 2-B Electron microscopy demonstrating apoptotic cells. N = nucleus and Cy = cytoplasm (original magnification, 4700). Fig. 2-B Apoptotic chondrocytes from a high-load explant. Note the shrinkage of the nucleus and the apoptotic cells and the presence of matrix vesicles (MV).
Anchor for JumpAnchor for Jump
+Fig. 4:Dose response. Explants were loaded at the intensities indicated. The number of cells demonstrating apoptosis compared with all visible cells was expressed as a percentage. Glycosaminoglycan (GAG) levels in the media were measured and expressed as a percentage of explant glycosaminoglycan content.
Anchor for JumpAnchor for Jump
+Fig. 5:Time-course of apoptosis. Explants were loaded at 30% strain for 500 msec and harvested at various time-points up to ninety-six hours. Apoptosis was measured as the percentage of cells staining positive.
TewSR, Kwan AP, Hann A, Thompson BM,Archer CW. The reactions of articular cartilage to experimental wounding: role of apoptosis. Arthritis Rheum,2000;41: 215-25. 41215  2000 
 
LoeningAM, James IE, Levenston ME, Badger AM, Frank EH, Kurz B, Nuttall ME, Hung HH, Blake SM, Grodzinsky AJ,Lark MW. Injurious mechanical compression of bovine articular cartilage induces chondrocyte apoptosis. Arch Biochem Biophys,2000;381: 205-12. 381205  2000  [PubMed]
 
D’Lima DD, Hashimoto S, Chen PC, Lotz MK,Colwell CW Jr. Prevention of chondrocyte apoptosisJ Bone Joint Surg Am200183(Suppl 2)25-26. J Bone Joint Surg Am,200183(Suppl 2)25-26;83(Suppl 2): 25-26. 83(Suppl 2)25  200183(Suppl 2)25-26 
 
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These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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