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

The Death Receptor 3/TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis
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). 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
0022-1007
2457-2464
Bull, Melanie Jane
c589ec9a-11d0-4e7e-9a1f-d4b90ddaeedd
Williams, Anwen Sian
b90c78b5-273d-4845-9a0e-e23758ec9218
Mecklenburgh, Zarabeth
b185d0b9-078d-4ae9-a965-32c38f38bd5d
Calder, Claudia Jane
d9cafd95-5f6f-4a0e-983a-915582ef1075
Twohig, Jason Peter
41eb7512-aaa6-416f-805e-17d08b59dfb2
Elford, Carole
7e811443-daa1-4cf3-a3b9-b98ab583d405
Evans, Bronwen Alice Jane
496915f1-8163-4c46-a447-e986f0fa260b
Rowley, Tania F.
3a29866f-3e2c-4ee8-8fe6-fd189ac1eb3d
Slebioda, Tomasz J.
f001a11a-78b8-4919-b105-4b0bb14d1d8e
Taraban, Vadim Y.
d709dcbb-ff36-4514-85da-08ca68aafcd3
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Wang, Eddie Chung
8573287f-8043-422a-80c0-81700926174d
Bull, Melanie Jane
c589ec9a-11d0-4e7e-9a1f-d4b90ddaeedd
Williams, Anwen Sian
b90c78b5-273d-4845-9a0e-e23758ec9218
Mecklenburgh, Zarabeth
b185d0b9-078d-4ae9-a965-32c38f38bd5d
Calder, Claudia Jane
d9cafd95-5f6f-4a0e-983a-915582ef1075
Twohig, Jason Peter
41eb7512-aaa6-416f-805e-17d08b59dfb2
Elford, Carole
7e811443-daa1-4cf3-a3b9-b98ab583d405
Evans, Bronwen Alice Jane
496915f1-8163-4c46-a447-e986f0fa260b
Rowley, Tania F.
3a29866f-3e2c-4ee8-8fe6-fd189ac1eb3d
Slebioda, Tomasz J.
f001a11a-78b8-4919-b105-4b0bb14d1d8e
Taraban, Vadim Y.
d709dcbb-ff36-4514-85da-08ca68aafcd3
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Wang, Eddie Chung
8573287f-8043-422a-80c0-81700926174d

Bull, Melanie Jane, Williams, Anwen Sian, Mecklenburgh, Zarabeth, Calder, Claudia Jane, Twohig, Jason Peter, Elford, Carole, Evans, Bronwen Alice Jane, Rowley, Tania F., Slebioda, Tomasz J., Taraban, Vadim Y., Al-Shamkhani, Aymen and Wang, Eddie Chung (2008) The Death Receptor 3/TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. The Journal of Experimental Medicine, 205 (11), 2457-2464. (doi:10.1084/jem.20072378). (PMID:18824582)

Record type: Article

Abstract

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

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Published date: October 2008
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 73437
URI: https://eprints.soton.ac.uk/id/eprint/73437
ISSN: 0022-1007
PURE UUID: 11c27326-9e58-4b0f-aa97-d0b259c5d644
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 09 Mar 2010
Last modified: 31 Jan 2019 01:37

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Contributors

Author: Melanie Jane Bull
Author: Anwen Sian Williams
Author: Zarabeth Mecklenburgh
Author: Claudia Jane Calder
Author: Jason Peter Twohig
Author: Carole Elford
Author: Bronwen Alice Jane Evans
Author: Tania F. Rowley
Author: Tomasz J. Slebioda
Author: Vadim Y. Taraban
Author: Eddie Chung Wang

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