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 4

Chondrocyte death following mechanical destabilization in the knee.

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Chondrocyte death following mechanical destabilization in the knee. (A) ...
(A) Representative H&E-stained coronal sections (left) and confocal images of DAPI-stained nuclei at depths of 20 μm (right, pseudocolored white) in medial and lateral condyles of 14-week-old mice that had undergone sham (upper) or DMM (lower) surgery at 10 weeks of age (n = 6). (B) Bar graphs depicting the mean (± SD) values for global cell density, superficial cell density, and cartilage thickness in condyles from 14-week-old mice that had undergone DMM surgery (red bars) or sham surgery (blue bars) 4 weeks earlier (n = 6). Note only the superficial cell density on the medial side of the medial condyle is lower in the DMM compared to shame treated mice. *P < 0.05 Student’s t test. (C) Representative H&E-stained coronal sections (left) and confocal images of DAPI-stained nuclei at depths of 20 μm (right, pseudocolored white) in medial and lateral condyles of 22-week-old mice that had undergone sham (upper) or DMM (lower) surgery at 10 weeks of age (n = 9). Note the appearance of surface roughening in both condyles and the reduction in the number of DAPI-stained nuclei in the medial, but not in the lateral, condyle of the DMM mice compared with sham-treated mice. (D) Bar graphs depicting the mean (± SD) values for global cell density, superficial cell density, and cartilage thickness in condyles from 22-week-old mice that had undergone DMM surgery (red bars) or sham surgery (blue bars) 12 weeks earlier (n = 9). Note the significant decrease in chondrocyte density in medial surface of the medial condyle. *P < 0.01, Student’s t test. The medial surface of the medial condyle is normally protected when the meniscus is intact. Scale bar: 50 μm.