The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis.
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). DR3(ko) 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 DR3(ko) 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.
Bull
Melanie Jane
MJ
Department of Medical Biochemistry and Immunology, School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.
Williams
Anwen Siân
AS
Mecklenburgh
Zarabeth
Z
Calder
Claudia Jane
CJ
Twohig
Jason Peter
JP
Elford
Carole
C
Evans
Bronwen Alice James
BA
Rowley
Tania F
TF
Slebioda
Tomasz J
TJ
Taraban
Vadim Y
VY
Al-Shamkhani
Aymen
A
Wang
Eddie Chung Yern
EC
D000818:Animals; D000911:Antibodies, Monoclonal; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology*; D001842:Bone and Bones / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000276:immunology; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018709:Statistics, Nonparametric; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15