Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis
Minjie Zhang, … , Gregory D. Jay, Matthew L. Warman
Minjie Zhang, … , Gregory D. Jay, Matthew L. Warman
Published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):2893-2902. https://doi.org/10.1172/JCI83676.
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Research Article Bone biology

Induced superficial chondrocyte death reduces catabolic cartilage damage in murine posttraumatic osteoarthritis

Abstract

Joints that have degenerated as a result of aging or injury contain dead chondrocytes and damaged cartilage. Some studies have suggested that chondrocyte death precedes cartilage damage, but how the loss of chondrocytes affects cartilage integrity is not clear. In this study, we examined whether chondrocyte death undermines cartilage integrity in aging and injury using a rapid 3D confocal cartilage imaging technique coupled with standard histology. We induced autonomous expression of diphtheria toxin to kill articular surface chondrocytes in mice and determined that chondrocyte death did not lead to cartilage damage. Moreover, cartilage damage after surgical destabilization of the medial meniscus of the knee was increased in mice with intact chondrocytes compared with animals whose chondrocytes had been killed, suggesting that chondrocyte death does not drive cartilage damage in response to injury. These data imply that chondrocyte catabolism, not death, contributes to articular cartilage damage following injury. Therefore, therapies targeted at reducing the catabolic phenotype may protect against degenerative joint disease.

Authors

Minjie Zhang, Sriniwasan B. Mani, Yao He, Amber M. Hall, Lin Xu, Yefu Li, David Zurakowski, Gregory D. Jay, Matthew L. Warman

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Figure 5

Chondrocyte loss prevents cartilage from being damaged by DMM surgery.

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Chondrocyte loss prevents cartilage from being damaged by DMM surgery. (...
(A) Representative confocal images of DAPI-stained nuclei at depths of 20 μm (pseudocolored white) in medial and lateral femoral condyles of mice that had undergone sham (upper) or DMM (lower) surgery 12 weeks earlier (n = 6). Scale bar: 100 μm. (B and C) Bar graphs depicting the mean (± SD) values for global cell density (B) and superficial density (C) in condyles from mice that had undergone DMM surgery (red bars) or sham surgery (blue bars) 12 weeks earlier (n = 6). Note the significant decrease in chondrocyte density in all condyles of the DTA mice compared with control mice. Also note that DMM surgery did not further affect chondrocyte density in the DTA-ablated mice, whereas cell density decreased significantly in the medial condyles of nonablated mice that underwent DMM versus sham surgery. *P < 0.05, control vs. DTA, Student’s t test. #P < 0.05, sham vs. DMM, Student’s t test. (D) H&E-stained coronal sections in medial femoral condyles (left) and medial tibial plateau (right) of 22-week-old mice that had undergone sham (upper) or DMM (lower) surgery 12 weeks earlier. Images are from the mouse with the median OARSI score in each group (n = 6). Scale bar: 50 μm. (E) OARSI scores of control or DTA-ablated mice that underwent sham or DMM surgery 12 weeks earlier (n = 6/group). Note the significantly higher OARSI score in DMM joints in both control and DTA mice versus sham joints and significantly lower OARSI score in DMM joints in DTA mice versus DMM joints in controls. *P < 0.05, control vs. DTA, nonparametric Wilcoxon rank-sum test. #P < 0.05, sham vs. DMM, nonparametric Wilcoxon rank-sum test.