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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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Protection against AIA in DR3ko mice. (A) Joint swelling after intraarticular injection of mBSA. Data are mean ± SEM from n = 6 DR3wt (▵) or DR3ko (▪) mice. Two-way analysis of variance (ANOVA) shows significance at P < 0.02 (*). One representative experiment of three is shown. (B–E) Representative images from DR3wt (B) and DR3ko (C) mice, 3 d after arthritis induction, and DR3wt (D) and DR3ko (E) mice, 21 d after arthritis induction. Bars, 200 μm. Inflammatory tissue (black arrowheads) and erosions (blue arrowheads) are shown. (F) Breakdown of each component of the AI. *, P < 0.05; **, P < 0.01. (G) AI scores from DR3wt and DR3ko mice. **, P < 0.01. Lines mark means of graphed points. (H and I) Representative images of collagen around knee joints from DR3wt (H) and DR3ko (I) mice. Sections were stained with Safranin O/Fast Green to visualize collagen in red. Tidemark of cartilage depletion (arrows) is shown. Bars, 50 μm. (J) Estimated cartilage depletion from DR3wt and DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single 6 DR3wt (▵) or DR3ko (▪) animal.
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fig1: Protection against AIA in DR3ko mice. (A) Joint swelling after intraarticular injection of mBSA. Data are mean ± SEM from n = 6 DR3wt (▵) or DR3ko (▪) mice. Two-way analysis of variance (ANOVA) shows significance at P < 0.02 (*). One representative experiment of three is shown. (B–E) Representative images from DR3wt (B) and DR3ko (C) mice, 3 d after arthritis induction, and DR3wt (D) and DR3ko (E) mice, 21 d after arthritis induction. Bars, 200 μm. Inflammatory tissue (black arrowheads) and erosions (blue arrowheads) are shown. (F) Breakdown of each component of the AI. *, P < 0.05; **, P < 0.01. (G) AI scores from DR3wt and DR3ko mice. **, P < 0.01. Lines mark means of graphed points. (H and I) Representative images of collagen around knee joints from DR3wt (H) and DR3ko (I) mice. Sections were stained with Safranin O/Fast Green to visualize collagen in red. Tidemark of cartilage depletion (arrows) is shown. Bars, 50 μm. (J) Estimated cartilage depletion from DR3wt and DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single 6 DR3wt (▵) or DR3ko (▪) animal.

Mentions: To investigate the in vivo role of DR3 in inflammatory arthritis, we induced AIA in DR3ko mice and DR3wt controls. All mice developed an inflammatory reaction in response to intraarticular injection of methylated BSA, with both DR3ko and DR3wt mice exhibiting a similar pattern of joint swelling over a 21-d time course. Comparable knee joint swelling measurements were noted in DR3ko and DR3wt mice at the peak of response, 1 d after mBSA injection. Thereafter, swelling resolved in both but faster in the absence of DR3 (Fig. 1 A).


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)

Protection against AIA in DR3ko mice. (A) Joint swelling after intraarticular injection of mBSA. Data are mean ± SEM from n = 6 DR3wt (▵) or DR3ko (▪) mice. Two-way analysis of variance (ANOVA) shows significance at P < 0.02 (*). One representative experiment of three is shown. (B–E) Representative images from DR3wt (B) and DR3ko (C) mice, 3 d after arthritis induction, and DR3wt (D) and DR3ko (E) mice, 21 d after arthritis induction. Bars, 200 μm. Inflammatory tissue (black arrowheads) and erosions (blue arrowheads) are shown. (F) Breakdown of each component of the AI. *, P < 0.05; **, P < 0.01. (G) AI scores from DR3wt and DR3ko mice. **, P < 0.01. Lines mark means of graphed points. (H and I) Representative images of collagen around knee joints from DR3wt (H) and DR3ko (I) mice. Sections were stained with Safranin O/Fast Green to visualize collagen in red. Tidemark of cartilage depletion (arrows) is shown. Bars, 50 μm. (J) Estimated cartilage depletion from DR3wt and DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single 6 DR3wt (▵) or DR3ko (▪) animal.
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fig1: Protection against AIA in DR3ko mice. (A) Joint swelling after intraarticular injection of mBSA. Data are mean ± SEM from n = 6 DR3wt (▵) or DR3ko (▪) mice. Two-way analysis of variance (ANOVA) shows significance at P < 0.02 (*). One representative experiment of three is shown. (B–E) Representative images from DR3wt (B) and DR3ko (C) mice, 3 d after arthritis induction, and DR3wt (D) and DR3ko (E) mice, 21 d after arthritis induction. Bars, 200 μm. Inflammatory tissue (black arrowheads) and erosions (blue arrowheads) are shown. (F) Breakdown of each component of the AI. *, P < 0.05; **, P < 0.01. (G) AI scores from DR3wt and DR3ko mice. **, P < 0.01. Lines mark means of graphed points. (H and I) Representative images of collagen around knee joints from DR3wt (H) and DR3ko (I) mice. Sections were stained with Safranin O/Fast Green to visualize collagen in red. Tidemark of cartilage depletion (arrows) is shown. Bars, 50 μm. (J) Estimated cartilage depletion from DR3wt and DR3ko mice. *, P < 0.05. Each point in the summary graphs represents a single 6 DR3wt (▵) or DR3ko (▪) animal.
Mentions: To investigate the in vivo role of DR3 in inflammatory arthritis, we induced AIA in DR3ko mice and DR3wt controls. All mice developed an inflammatory reaction in response to intraarticular injection of methylated BSA, with both DR3ko and DR3wt mice exhibiting a similar pattern of joint swelling over a 21-d time course. Comparable knee joint swelling measurements were noted in DR3ko and DR3wt mice at the peak of response, 1 d after mBSA injection. Thereafter, swelling resolved in both but faster in the absence of DR3 (Fig. 1 A).

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