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

Wang, Eddie C. Y. ORCID:, Newton, Zarabeth, Hayward, Olivia A., Clark, Stephen R. ORCID:, Collins, Fraser, Perks, William V., Singh, Ravinder K., Twohig, Jason P. and Williams, Anwen S. ORCID: 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: 21 Sep 2023 17:40

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