Regulation of Early Cartilage Destruction in Inflammatory Arthritis by Death Receptor 3

Eddie C.Y. Wang, Zarabeth Newton, Olivia A. Hayward, Stephen R. Clark, Fraser Collins, William V. Perks, Ravinder K. Singh, Jason P. Twohig, Anwen S. Williams

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective

To investigate the role of death receptor 3 (DR‐3) and its ligand tumor necrosis factor–like molecule 1A (TL1A) in the early stages of inflammatory arthritis.

Methods

Antigen‐induced arthritis (AIA) was generated in C57BL/6 mice deficient in the DR‐3 gene (DR3−/−) and their DR3+/+ (wild‐type) littermates by priming and intraarticular injection of methylated bovine serum albumin. The joints were sectioned and analyzed histochemically for damage to cartilage and expression of DR3, TL1A, Ly‐6G (a marker for neutrophils), the gelatinase matrix metalloproteinase 9 (MMP‐9), the aggrecanase ADAMTS‐5, and the neutrophil chemoattractant CXCL1. In vitro production of MMP‐9 was measured in cultures from fibroblasts, macrophages, and neutrophils following the addition of TL1A and other proinflammatory stimuli.

Results

DR3 expression was up‐regulated in the joints of wild‐type mice following generation of AIA. DR3−/− mice were protected against cartilage damage compared with wild‐type mice, even at early time points prior to the main accumulation of Teff cells in the joint. Early protection against AIA in vivo correlated with reduced levels of MMP‐9. In vitro, neutrophils were major producers of MMP‐9, while neutrophil numbers were reduced in the joints of DR3−/− mice. However, TL1A neither induced MMP‐9 release nor affected the survival of neutrophils. Instead, reduced levels of CXCL1 were observed in the joints of DR3−/− mice.

Conclusion

DR‐3 drives early cartilage destruction in the AIA model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint and leading to enhanced local production of cartilage‐destroying enzymes.

Original languageEnglish
Pages (from-to)2762-2772
Number of pages11
JournalArthritis & Rheumatology
Volume66
Issue number10
Early online date26 Sep 2014
DOIs
Publication statusPublished - Oct 2014

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  • Cite this

    Wang, E. C. Y., Newton, Z., Hayward, O. A., Clark, S. R., Collins, F., Perks, W. V., Singh, R. K., Twohig, J. P., & Williams, A. S. (2014). Regulation of Early Cartilage Destruction in Inflammatory Arthritis by Death Receptor 3. Arthritis & Rheumatology, 66(10), 2762-2772. https://doi.org/10.1002/art.38770