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Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3

Wang, Eddie C. Y., Newton, Zarabeth, Hayward, Olivia A., Clark, Stephen R., Collins, Fraser, Perks, William V., Singh, Ravinder K., Twohig, Jason P. and Williams, Anwen S. 2014. Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3. Arthritis and Rheumatology 66 (10) , pp. 2762-2772. 10.1002/art.38770

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Publisher: Wiley
ISSN: 2326-5191
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 26 June 2014
Last Modified: 28 May 2020 11:30

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