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 3

Preservation of cartilage surfaces despite DTA-induced killing of surface chondrocytes.

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Preservation of cartilage surfaces despite DTA-induced killing of surfac...
(A) Schematic depicting the experimental timeline for inducing cell death with tamoxifen-mediated induction of DTA expression from 21 to 30 days of age. Subsequent cell division was monitored by administering EdU from 31 to 40 days of age or from 2 to 3 months of age. (B, D, and F) Representative H&E-stained sagittal sections through the tibial-femoral joint of 40-day-old (B), 3-month-old (D), and 9-month-old (F) control mice (left) and DTA-ablated mice (right) (n = 5/time point). (C, E, and G) Representative Safranin O– and Fast Green stained sagittal sections through the tibial-femoral joint of 40-day-old (C), 3-month-old (E), and 9-month-old (G) control mice (left) and DTA-ablated mice (right) (n = 5/time point). Scale bars: 50 μm. (H and I) Bar graphs depicting the mean (± SD) global cell densities and superficial cell densities in the lateral condyle (H) and femoral head (I) of control (blue bars) and DTA-ablated (red bars) mice at different time points (n = 5/time point). Note chondrocyte density measured globally and in the superficial zone decreased significantly in 40-day-old and 3-month-old DTA-ablated mice compared with controls, with the greatest decrease occurring in the superficial zone. However, this decrease disappeared at 9 months of age. *P < 0.05, Student’s t test. (J) Representative histograms depicting the distribution of nearest neighbor distances for DAPI-stained nuclei in the femoral heads of 9-month-old control (upper) and DTA-ablated (lower) mice. Note the significantly increased mean distance in the DTA-ablated mice (P < 0.001, Student’s t test, n = 5) and the significant difference in the histogram shape (P = 0.023, Levene’s test) between control and DTA-ablated mice. (K) Bar graphs depicting mean (± SD) percentages of DAPI-stained chondrocyte nuclei that are also EdU positive (n = 5). Note the DTA-ablated mice (red bars) exhibit significantly lower percentages of EdU-positive cells at 40 days of age compared with control mice (blue bars), but significantly higher percentages of EdU-positive cells at 3 months of age. *P < 0.05, Student’s t test.