title: CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss.
abstract: Reduced bone density and secondary osteoporosis, resulting in increased risk of fracture, is a significant complicating factor in the inflammatory arthritides. While the exact etiology of systemic bone loss is not fully elucidated, recent insights into the tumor necrosis factor super family (TNFSF) revealed a potential role for death receptor 3 (DR3/TNFRSF25) and one of its ligands, TNF-like protein 1A (TL1A/TNFSF15). The mechanisms by which DR3/TL1A signalling modulates bone loss are unclear. We investigated the effect of DR3/TL1A signalling upon osteoclast-dependent chemokine and MMP production to unravel novel mechanisms whereby this pathway regulates OC formation and OC-dependent bone resorption. Collagen induced arthritis (CIA) was established in DR3wtand DR3komice, joints were sectioned and analysed histologically for bone damage while systemic trabecular bone loss distal to the affected joints was compared by micro-CT. Ablation of DR3 protected DBA/1 mice against the development and progression of CIA. In DR3ko, joints of the ankle and mid-foot were almost free of bone erosions and long bones of mice with CIA were protected against systemic trabecular bone loss. In vitro, expression of DR3 was confirmed on primary human CD14+osteoclast precursors by flow cytometry. These cells were treated with TL1A in osteoclast differentiation medium and TRAP+osteoclasts, bone resorption, levels of osteoclast-associated chemokines (CCL3, CCL2 and CXCL8) and MMP-9 measured. TL1A intensified human osteoclast differentiation and bone resorption and increased osteoclast-associated production of CCL3 and MMP-9. Our data reveals the DR3 pathway as an attractive therapeutic target to combat adverse bone pathology associated with inflammatory arthritis. We demonstrate that DR3 is critical in the pathogenesis of murine CIA and associated secondary osteoporosis. Furthermore, we identify a novel mechanism by which the DR3/TL1A pathway directly enhances human OC formation and resorptive activity, controlling expression and activation of CCL3 and MMP-9.
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: Fraser L
authors.initials: FL
authors.lastname: Collins
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Jessica O
authors.initials: JO
authors.lastname: Williams
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Bloom
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Jordan
authors.affiliation: University Hospital Llandough, Cardiff & Vale University Health Board, Cardiff, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Stone
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA; Department of Radiology, Michigan State University, East Lansing, MI, USA; Biomedical Imaging Research Centre, Michigan State University, East Lansing, MI, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: McCabe
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address: wangec@cf.ac.uk.
authors.forename: Eddie C Y
authors.initials: ECY
authors.lastname: Wang
authors.affiliation: Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom. Electronic address: williamsas@cf.ac.uk.
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D000071556:Cancellous Bone / Q000473:pathology; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D054405:Chemokine CCL3; D018950:Lipopolysaccharide Receptors; D053245:RANK Ligand; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D020780:Matrix Metalloproteinase 9
keywords: CCL3; Collagen-induced arthritis; MMP-9; Osteoclast; Osteoporosis; TNFRSF25; TNFSF15