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A functional role for death receptor-3 in arthritis

A functional role for death receptor-3 in arthritis
A functional role for death receptor-3 in arthritis
TNF-like protein 1A (TL1A) ligation with death receptor-3 (DR3), a death domain containing member of the tumour necrosis factor receptor superfamily, activates multiple target cell responses. Published genetic and serological data implicate DR3 in rheumatoid arthritis, a chronic inflammatory joint disease. DR3’s function in rheumatoid arthritis has not been established. We question whether; DR3/TL1A activation triggers adverse joint pathology during inflammatory arthritis. We used two murine experimental arthritis models, antigen-induced arthritis (mAIA) and collagen-induced arthritis (mCIA), to study the histological progression of DR3 dependent joint pathology. Osteoclast differentiation assays were performed on both human and mouse macrophages. Osteoclast numbers were quantified in vivo and in vitro by tartrate resistant acid phosphatase staining. In the mAIA model all disease activity indices were significantly reduced in DR3-deficient mice (DR3ko) over age-matched DR3-sufficient wild-type littermate controls. Most striking was the fact that DR3ko were completely protected from the development of the focal bone erosions characteristically seen in mAIA. Add-back experiments with TL1A confirmed that bone pathology was a DR3 specific phenomenon. Our in vitro osteoclast differentiation assays revealed a potential mechanism. We observed heightened DR3-specific osteoclastogenesis in mouse and human macrophage cultures. Osteoclasts are unique in their ability to resorb bone. Finally, we tested the therapeutic efficacy of DR3 antagonism using a TL1A blocking antibody. We found that anti-TL1A significantly reduced the incidence and severity of mCIA. Indeed arthritis was virtually ameliorated at endpoint; all disease activity scores were significantly reduced in anti-TL1A treated mice. Our study reveals the DR3/TL1A axis as an important trigger for adverse joint pathology during inflammatory arthritis and an important regulator of bone turnover. We provide proof-of-concept data which identifies DR3/TL1A antagonism as a potential target to modulate pathology in bone disease and inflammatory arthritis
1043-4666
134
Williams, Anwen S.
f75f55e5-c20c-4bde-b708-6076ddcbbacb
Bull, Melanie J.
9a5dbfdf-ad97-4ecb-aace-8dc39636d5b1
Mecklenburgh, Zarabeth
b185d0b9-078d-4ae9-a965-32c38f38bd5d
Calder, Claudia J.
c0f613cc-85c6-4cd2-9553-0d66579558db
Twohig, Jason P.
c070435e-a474-4a88-8213-14dd22bb743b
Elford, Carole
7e811443-daa1-4cf3-a3b9-b98ab583d405
Evans, Bronwen
581b470f-c3fc-4a61-ae9e-28f6e631cdaf
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Wang, Eddie
4e5a0e5d-5ea8-46dd-9930-6acb6b217248
Williams, Anwen S.
f75f55e5-c20c-4bde-b708-6076ddcbbacb
Bull, Melanie J.
9a5dbfdf-ad97-4ecb-aace-8dc39636d5b1
Mecklenburgh, Zarabeth
b185d0b9-078d-4ae9-a965-32c38f38bd5d
Calder, Claudia J.
c0f613cc-85c6-4cd2-9553-0d66579558db
Twohig, Jason P.
c070435e-a474-4a88-8213-14dd22bb743b
Elford, Carole
7e811443-daa1-4cf3-a3b9-b98ab583d405
Evans, Bronwen
581b470f-c3fc-4a61-ae9e-28f6e631cdaf
Al-Shamkhani, Aymen
0a40b3ce-9d71-4d41-9369-7212f0a84504
Wang, Eddie
4e5a0e5d-5ea8-46dd-9930-6acb6b217248

Williams, Anwen S., Bull, Melanie J., Mecklenburgh, Zarabeth, Calder, Claudia J., Twohig, Jason P., Elford, Carole, Evans, Bronwen, Al-Shamkhani, Aymen and Wang, Eddie (2009) A functional role for death receptor-3 in arthritis. Cytokine, 48 (1-2), 134. (doi:10.1016/j.cyto.2009.07.568).

Record type: Article

Abstract

TNF-like protein 1A (TL1A) ligation with death receptor-3 (DR3), a death domain containing member of the tumour necrosis factor receptor superfamily, activates multiple target cell responses. Published genetic and serological data implicate DR3 in rheumatoid arthritis, a chronic inflammatory joint disease. DR3’s function in rheumatoid arthritis has not been established. We question whether; DR3/TL1A activation triggers adverse joint pathology during inflammatory arthritis. We used two murine experimental arthritis models, antigen-induced arthritis (mAIA) and collagen-induced arthritis (mCIA), to study the histological progression of DR3 dependent joint pathology. Osteoclast differentiation assays were performed on both human and mouse macrophages. Osteoclast numbers were quantified in vivo and in vitro by tartrate resistant acid phosphatase staining. In the mAIA model all disease activity indices were significantly reduced in DR3-deficient mice (DR3ko) over age-matched DR3-sufficient wild-type littermate controls. Most striking was the fact that DR3ko were completely protected from the development of the focal bone erosions characteristically seen in mAIA. Add-back experiments with TL1A confirmed that bone pathology was a DR3 specific phenomenon. Our in vitro osteoclast differentiation assays revealed a potential mechanism. We observed heightened DR3-specific osteoclastogenesis in mouse and human macrophage cultures. Osteoclasts are unique in their ability to resorb bone. Finally, we tested the therapeutic efficacy of DR3 antagonism using a TL1A blocking antibody. We found that anti-TL1A significantly reduced the incidence and severity of mCIA. Indeed arthritis was virtually ameliorated at endpoint; all disease activity scores were significantly reduced in anti-TL1A treated mice. Our study reveals the DR3/TL1A axis as an important trigger for adverse joint pathology during inflammatory arthritis and an important regulator of bone turnover. We provide proof-of-concept data which identifies DR3/TL1A antagonism as a potential target to modulate pathology in bone disease and inflammatory arthritis

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Published date: October 2009

Identifiers

Local EPrints ID: 153681
URI: http://eprints.soton.ac.uk/id/eprint/153681
ISSN: 1043-4666
PURE UUID: 1c28ea00-c5e8-4f60-bca6-53030339c971
ORCID for Aymen Al-Shamkhani: ORCID iD orcid.org/0000-0003-0727-4189

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Date deposited: 20 May 2010 15:37
Last modified: 14 Mar 2024 02:42

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Contributors

Author: Anwen S. Williams
Author: Melanie J. Bull
Author: Zarabeth Mecklenburgh
Author: Claudia J. Calder
Author: Jason P. Twohig
Author: Carole Elford
Author: Bronwen Evans
Author: Eddie Wang

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