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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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Early therapeutic intervention with anti-TL1A antibody arrests development of arthritis. (A) Binding of rat anti-TL1A mAb (TAN 2–2) to J558L cells transfected with plasmid encoding membrane-bound TL1A. Shaded histogram and dotted line represent binding of isotype control and TAN 2–2 to plasmid only transfected cells, respectively. Binding of isotype control and TAN 2–2 to TL1A-expressing cells is represented by a thin and thick line, respectively. (B) Titration of TAN 2–2 binding to J558L cells expressing membrane-bound TL1A. (C) Time course of swelling in AIA after anti-TL1A mAb treatment. Data are mean ± SEM from mice treated with control IgG2A (▴) or anti-TL1A (▿) mAb. One representative experiment of two is shown. *, P < 0.02 by two-way ANOVA. CIA was induced as described in Materials and methods. All data were derived from six mice for each treatment. (D) Arthritis incidence tabulated over 28-d time course. (E) Arthritis severity as a mean paw score from day 20 when dosing schedule for anti-TL1A and control IgG2a was started. Data are mean ± SEM. Timing of injections are shown (arrows). (F and G) Representative images of H&E-stained sections from control IgG2a (F) and anti-TL1A (G). i, intense synovial infiltration; e, aggressive bone erosion. Bars, 200 μm. (H) Analysis of AI of CIA in control IgG2a and anti-TL1A–treated mice. Dotted horizontal line depicts mean for each group. *, P < 0.05; **, P = 0.01; ***, P = 0.006.
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fig5: Early therapeutic intervention with anti-TL1A antibody arrests development of arthritis. (A) Binding of rat anti-TL1A mAb (TAN 2–2) to J558L cells transfected with plasmid encoding membrane-bound TL1A. Shaded histogram and dotted line represent binding of isotype control and TAN 2–2 to plasmid only transfected cells, respectively. Binding of isotype control and TAN 2–2 to TL1A-expressing cells is represented by a thin and thick line, respectively. (B) Titration of TAN 2–2 binding to J558L cells expressing membrane-bound TL1A. (C) Time course of swelling in AIA after anti-TL1A mAb treatment. Data are mean ± SEM from mice treated with control IgG2A (▴) or anti-TL1A (▿) mAb. One representative experiment of two is shown. *, P < 0.02 by two-way ANOVA. CIA was induced as described in Materials and methods. All data were derived from six mice for each treatment. (D) Arthritis incidence tabulated over 28-d time course. (E) Arthritis severity as a mean paw score from day 20 when dosing schedule for anti-TL1A and control IgG2a was started. Data are mean ± SEM. Timing of injections are shown (arrows). (F and G) Representative images of H&E-stained sections from control IgG2a (F) and anti-TL1A (G). i, intense synovial infiltration; e, aggressive bone erosion. Bars, 200 μm. (H) Analysis of AI of CIA in control IgG2a and anti-TL1A–treated mice. Dotted horizontal line depicts mean for each group. *, P < 0.05; **, P = 0.01; ***, P = 0.006.

Mentions: To test the therapeutic potential of countering the DR3–TL1A pathway, we generated an antagonistic rat mAb to murine TL1A (Fig. 5, A and B) and applied it in AIA and the systemic model of disease. CIA is the industry standard for testing potential therapeutic agents against RA. A single treatment of anti-TL1A at the point of arthritic induction in AIA resulted in more rapid resolution of swelling that mirrored our observations in DR3ko mice (Fig. 5 C). In CIA, clinical signs of arthritis became apparent in control mice on day 25 (Fig. 5 D). Disease activity was assessed by assigning scores to each paw according to degree of redness, swelling, and joint involvement. Paw scores in anti-TL1A–treated mice were consistently lower than in control IgG2a-treated mice, reaching significance on days 27 and 28 (Fig. 5 E). Disease activity in control IgG2a-treated mice was characterized by leukocyte infiltration of synovial tissues and variable degrees of bone erosion (Fig. 5 F). Specimens from anti-TL1A–treated mice demonstrated mild changes by comparison (Fig. 5 G). The AI in anti-TL1A–treated mice was significantly less than in IgG2a-treated controls (Fig. 5 H). These data are consistent with the protection against AIA observed in DR3ko mice and suggest that countering the DR3–TL1A pathway may be therapeutic against RA in man.


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)

Early therapeutic intervention with anti-TL1A antibody arrests development of arthritis. (A) Binding of rat anti-TL1A mAb (TAN 2–2) to J558L cells transfected with plasmid encoding membrane-bound TL1A. Shaded histogram and dotted line represent binding of isotype control and TAN 2–2 to plasmid only transfected cells, respectively. Binding of isotype control and TAN 2–2 to TL1A-expressing cells is represented by a thin and thick line, respectively. (B) Titration of TAN 2–2 binding to J558L cells expressing membrane-bound TL1A. (C) Time course of swelling in AIA after anti-TL1A mAb treatment. Data are mean ± SEM from mice treated with control IgG2A (▴) or anti-TL1A (▿) mAb. One representative experiment of two is shown. *, P < 0.02 by two-way ANOVA. CIA was induced as described in Materials and methods. All data were derived from six mice for each treatment. (D) Arthritis incidence tabulated over 28-d time course. (E) Arthritis severity as a mean paw score from day 20 when dosing schedule for anti-TL1A and control IgG2a was started. Data are mean ± SEM. Timing of injections are shown (arrows). (F and G) Representative images of H&E-stained sections from control IgG2a (F) and anti-TL1A (G). i, intense synovial infiltration; e, aggressive bone erosion. Bars, 200 μm. (H) Analysis of AI of CIA in control IgG2a and anti-TL1A–treated mice. Dotted horizontal line depicts mean for each group. *, P < 0.05; **, P = 0.01; ***, P = 0.006.
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fig5: Early therapeutic intervention with anti-TL1A antibody arrests development of arthritis. (A) Binding of rat anti-TL1A mAb (TAN 2–2) to J558L cells transfected with plasmid encoding membrane-bound TL1A. Shaded histogram and dotted line represent binding of isotype control and TAN 2–2 to plasmid only transfected cells, respectively. Binding of isotype control and TAN 2–2 to TL1A-expressing cells is represented by a thin and thick line, respectively. (B) Titration of TAN 2–2 binding to J558L cells expressing membrane-bound TL1A. (C) Time course of swelling in AIA after anti-TL1A mAb treatment. Data are mean ± SEM from mice treated with control IgG2A (▴) or anti-TL1A (▿) mAb. One representative experiment of two is shown. *, P < 0.02 by two-way ANOVA. CIA was induced as described in Materials and methods. All data were derived from six mice for each treatment. (D) Arthritis incidence tabulated over 28-d time course. (E) Arthritis severity as a mean paw score from day 20 when dosing schedule for anti-TL1A and control IgG2a was started. Data are mean ± SEM. Timing of injections are shown (arrows). (F and G) Representative images of H&E-stained sections from control IgG2a (F) and anti-TL1A (G). i, intense synovial infiltration; e, aggressive bone erosion. Bars, 200 μm. (H) Analysis of AI of CIA in control IgG2a and anti-TL1A–treated mice. Dotted horizontal line depicts mean for each group. *, P < 0.05; **, P = 0.01; ***, P = 0.006.
Mentions: To test the therapeutic potential of countering the DR3–TL1A pathway, we generated an antagonistic rat mAb to murine TL1A (Fig. 5, A and B) and applied it in AIA and the systemic model of disease. CIA is the industry standard for testing potential therapeutic agents against RA. A single treatment of anti-TL1A at the point of arthritic induction in AIA resulted in more rapid resolution of swelling that mirrored our observations in DR3ko mice (Fig. 5 C). In CIA, clinical signs of arthritis became apparent in control mice on day 25 (Fig. 5 D). Disease activity was assessed by assigning scores to each paw according to degree of redness, swelling, and joint involvement. Paw scores in anti-TL1A–treated mice were consistently lower than in control IgG2a-treated mice, reaching significance on days 27 and 28 (Fig. 5 E). Disease activity in control IgG2a-treated mice was characterized by leukocyte infiltration of synovial tissues and variable degrees of bone erosion (Fig. 5 F). Specimens from anti-TL1A–treated mice demonstrated mild changes by comparison (Fig. 5 G). The AI in anti-TL1A–treated mice was significantly less than in IgG2a-treated controls (Fig. 5 H). These data are consistent with the protection against AIA observed in DR3ko mice and suggest that countering the DR3–TL1A pathway may be therapeutic against RA in man.

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