The Journal of Experimental Medicine
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Published online September 29, 2008
doi:10.1084/jem.20072378
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Bull et al.
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BRIEF DEFINITIVE REPORT

 The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Melanie Jane Bull1, Anwen Siân Williams2, Zarabeth Mecklenburgh1, Claudia Jane Calder1, Jason Peter Twohig1, Carole Elford3, Bronwen Alice James Evans3, Tania F. Rowley4, Tomasz J. Slebioda4, Vadim Y. Taraban4, Aymen Al-Shamkhani4, and Eddie Chung Yern Wang1

1 Department of Medical Biochemistry and Immunology, 2 Department of Rheumatology, and 3 Department of Child Health, School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK
4 Cancer Sciences Division, University of Southampton School of Medicine, Southampton SO16 6YD, England, UK

CORRESPONDENCE Eddie Chung Yern Wang: WangEC{at}cf.ac.uk

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.

M.J. Bull and A.S. Williams contributed equally to this paper.

© 2008 Bull et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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