title: Regulation of early cartilage destruction in inflammatory arthritis by death receptor 3.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiff Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, Wales, UK.
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.forename: Zarabeth
authors.initials: Z
authors.lastname: Newton
authors.forename: Olivia A
authors.initials: OA
authors.lastname: Hayward
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Clark
authors.forename: Fraser
authors.initials: F
authors.lastname: Collins
authors.forename: William V
authors.initials: WV
authors.lastname: Perks
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Singh
authors.forename: Jason P
authors.initials: JP
authors.lastname: Twohig
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D054360:Chemokine CXCL1 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism*
chemical_list: D054360:Chemokine CXCL1; D053219:Receptors, Tumor Necrosis Factor, Member 25; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15