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

Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP, Elford C, Evans BA, Rowley TF, Slebioda TJ, Taraban VY, Al-Shamkhani A, Wang EC - J. Exp. Med. (2008)

Bottom Line: In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Immunology, School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.

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). 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.

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TL1A promotes adverse bone pathology of AIA in a DR3-dependent manner. (A) AI with increasing administration of TL1A in DR3het mice. Horizontal lines mark means of graphed points. Open symbols represent DR3het mice; filled symbols represent DR3ko mice. (B and C) Representative images from DR3het mice with no (B) or 100 ng (C) TL1A added. Bone erosions (arrowheads) are shown. (D) AI with increasing administration of TL1A to DR3ko mice. (E and F) Representative images from DR3ko mice with 1 (E) or 100 (F) ng TL1A added. Bars, 200 μm. One-way ANOVA showed significance of TL1A addition to DR3het but not DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single animal. One representative experiment of two is shown.
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fig2: TL1A promotes adverse bone pathology of AIA in a DR3-dependent manner. (A) AI with increasing administration of TL1A in DR3het mice. Horizontal lines mark means of graphed points. Open symbols represent DR3het mice; filled symbols represent DR3ko mice. (B and C) Representative images from DR3het mice with no (B) or 100 ng (C) TL1A added. Bone erosions (arrowheads) are shown. (D) AI with increasing administration of TL1A to DR3ko mice. (E and F) Representative images from DR3ko mice with 1 (E) or 100 (F) ng TL1A added. Bars, 200 μm. One-way ANOVA showed significance of TL1A addition to DR3het but not DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single animal. One representative experiment of two is shown.

Mentions: To confirm that resistance to AIA was DR3 specific, TL1A was injected with mBSA on day 0 of the AIA model at escalating quantities up to 100 ng. DR3het mice were chosen as they showed intermediate AI scores compared with DR3wt mice (Figs. 1 G and 2 A). Consequently, exacerbation or amelioration of disease after TL1A injection could be quantified, irrespective of the inherent variability in the model. Coadministration of TL1A resulted in significant dose-dependent exacerbation of disease in DR3het mice (Fig. 2 A). This was strikingly illustrated by the effect on size of bone erosions and severity of bone destruction, which increased in a dose-dependent fashion after TL1A injection (Fig. 2, B and C). In contrast, TL1A had no significant effect on arthritis progression in DR3ko mice over the concentration range studied (Fig. 2 D). Representative images of DR3ko mice receiving 1 and 100 ng TL1A show the continued absence of bone erosions (Fig. 2, E and F). TL1A therefore exacerbates AIA and, in particular, adverse bone pathology in a DR3-dependent manner.


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

Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP, Elford C, Evans BA, Rowley TF, Slebioda TJ, Taraban VY, Al-Shamkhani A, Wang EC - J. Exp. Med. (2008)

TL1A promotes adverse bone pathology of AIA in a DR3-dependent manner. (A) AI with increasing administration of TL1A in DR3het mice. Horizontal lines mark means of graphed points. Open symbols represent DR3het mice; filled symbols represent DR3ko mice. (B and C) Representative images from DR3het mice with no (B) or 100 ng (C) TL1A added. Bone erosions (arrowheads) are shown. (D) AI with increasing administration of TL1A to DR3ko mice. (E and F) Representative images from DR3ko mice with 1 (E) or 100 (F) ng TL1A added. Bars, 200 μm. One-way ANOVA showed significance of TL1A addition to DR3het but not DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single animal. One representative experiment of two is shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2571920&req=5

fig2: TL1A promotes adverse bone pathology of AIA in a DR3-dependent manner. (A) AI with increasing administration of TL1A in DR3het mice. Horizontal lines mark means of graphed points. Open symbols represent DR3het mice; filled symbols represent DR3ko mice. (B and C) Representative images from DR3het mice with no (B) or 100 ng (C) TL1A added. Bone erosions (arrowheads) are shown. (D) AI with increasing administration of TL1A to DR3ko mice. (E and F) Representative images from DR3ko mice with 1 (E) or 100 (F) ng TL1A added. Bars, 200 μm. One-way ANOVA showed significance of TL1A addition to DR3het but not DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single animal. One representative experiment of two is shown.
Mentions: To confirm that resistance to AIA was DR3 specific, TL1A was injected with mBSA on day 0 of the AIA model at escalating quantities up to 100 ng. DR3het mice were chosen as they showed intermediate AI scores compared with DR3wt mice (Figs. 1 G and 2 A). Consequently, exacerbation or amelioration of disease after TL1A injection could be quantified, irrespective of the inherent variability in the model. Coadministration of TL1A resulted in significant dose-dependent exacerbation of disease in DR3het mice (Fig. 2 A). This was strikingly illustrated by the effect on size of bone erosions and severity of bone destruction, which increased in a dose-dependent fashion after TL1A injection (Fig. 2, B and C). In contrast, TL1A had no significant effect on arthritis progression in DR3ko mice over the concentration range studied (Fig. 2 D). Representative images of DR3ko mice receiving 1 and 100 ng TL1A show the continued absence of bone erosions (Fig. 2, E and F). TL1A therefore exacerbates AIA and, in particular, adverse bone pathology in a DR3-dependent manner.

Bottom Line: In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Immunology, School of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK.

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). 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.

Show MeSH
Related in: MedlinePlus