Limits...
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.

Show MeSH

Related in: MedlinePlus

TRAP and F4/80 expression in joints of DR3wt and DR3ko mice. Sections were stained for TRAP or F4/80 as described in Materials and methods. Horizontal lines mark means of graphed points. (A and B) Representative images of TRAP staining at day 21 after arthritic induction from DR3wt (A) and DR3ko (B) mice. Red TRAP+ staining (arrows) is shown. (C) Summary of TRAP staining in femoral head at day 21. (D and E) Representative images of TRAP staining around areas of bone erosion at day 21 after arthritic induction from DR3wt mice (D) and equivalent areas from DR3ko mice (E). Red TRAP+ staining (arrows) is shown; js, joint space; p, pannus; c, cartilage. (F) DR3ko mice show significantly reduced TRAP+ staining compared with DR3wt mice. *, P < 0.05. (G and H) Representative images of F4/80 staining from DR3wt (G) and DR3ko (H) mice, 3 d after arthritis induction. (I) Summary of day-3 data. (J and K) Representative images of F4/80 staining from DR3wt (J) and DR3ko (K) mice, 21 d after induction of arthritis. F4/80-positive cells (arrows) are shown. (L) Summary of day-21 data. Each point in the summary graphs represents a single DR3wt (▵) or DR3ko (▪) animal. Bars, 50 μm. One representative experiment of two is shown.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC2571920&req=5

fig3: TRAP and F4/80 expression in joints of DR3wt and DR3ko mice. Sections were stained for TRAP or F4/80 as described in Materials and methods. Horizontal lines mark means of graphed points. (A and B) Representative images of TRAP staining at day 21 after arthritic induction from DR3wt (A) and DR3ko (B) mice. Red TRAP+ staining (arrows) is shown. (C) Summary of TRAP staining in femoral head at day 21. (D and E) Representative images of TRAP staining around areas of bone erosion at day 21 after arthritic induction from DR3wt mice (D) and equivalent areas from DR3ko mice (E). Red TRAP+ staining (arrows) is shown; js, joint space; p, pannus; c, cartilage. (F) DR3ko mice show significantly reduced TRAP+ staining compared with DR3wt mice. *, P < 0.05. (G and H) Representative images of F4/80 staining from DR3wt (G) and DR3ko (H) mice, 3 d after arthritis induction. (I) Summary of day-3 data. (J and K) Representative images of F4/80 staining from DR3wt (J) and DR3ko (K) mice, 21 d after induction of arthritis. F4/80-positive cells (arrows) are shown. (L) Summary of day-21 data. Each point in the summary graphs represents a single DR3wt (▵) or DR3ko (▪) animal. Bars, 50 μm. One representative experiment of two is shown.

Mentions: Because DR3ko mice were protected from the development of subchondral bone erosions in AIA, we elected to quantify the number of bone-resorbing osteoclasts within the joint at two distinct sites of epiphyseal bone. Osteoclasts are clearly visualized as large red multinucleated cells with tartrate-resistant acid phosphatase (TRAP). TRAP expression in DR3wt and DR3ko mice was comparable in the femoral head (Fig. 3, A–C) and growth plate (not depicted). However, in the periosteum at areas adjacent to pannus formation, where focal bone erosions could be visualized at high magnification, TRAP staining was significantly greater in DR3wt mice than at equivalent areas in DR3ko mice (Fig. 3, D–F). These data implicate a role for DR3 in generation of osteoclasts at sites of bone pathology but not in influencing osteoclastogenesis in areas away from the pannus.


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)

TRAP and F4/80 expression in joints of DR3wt and DR3ko mice. Sections were stained for TRAP or F4/80 as described in Materials and methods. Horizontal lines mark means of graphed points. (A and B) Representative images of TRAP staining at day 21 after arthritic induction from DR3wt (A) and DR3ko (B) mice. Red TRAP+ staining (arrows) is shown. (C) Summary of TRAP staining in femoral head at day 21. (D and E) Representative images of TRAP staining around areas of bone erosion at day 21 after arthritic induction from DR3wt mice (D) and equivalent areas from DR3ko mice (E). Red TRAP+ staining (arrows) is shown; js, joint space; p, pannus; c, cartilage. (F) DR3ko mice show significantly reduced TRAP+ staining compared with DR3wt mice. *, P < 0.05. (G and H) Representative images of F4/80 staining from DR3wt (G) and DR3ko (H) mice, 3 d after arthritis induction. (I) Summary of day-3 data. (J and K) Representative images of F4/80 staining from DR3wt (J) and DR3ko (K) mice, 21 d after induction of arthritis. F4/80-positive cells (arrows) are shown. (L) Summary of day-21 data. Each point in the summary graphs represents a single DR3wt (▵) or DR3ko (▪) animal. Bars, 50 μm. One representative experiment of two is shown.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571920&req=5

fig3: TRAP and F4/80 expression in joints of DR3wt and DR3ko mice. Sections were stained for TRAP or F4/80 as described in Materials and methods. Horizontal lines mark means of graphed points. (A and B) Representative images of TRAP staining at day 21 after arthritic induction from DR3wt (A) and DR3ko (B) mice. Red TRAP+ staining (arrows) is shown. (C) Summary of TRAP staining in femoral head at day 21. (D and E) Representative images of TRAP staining around areas of bone erosion at day 21 after arthritic induction from DR3wt mice (D) and equivalent areas from DR3ko mice (E). Red TRAP+ staining (arrows) is shown; js, joint space; p, pannus; c, cartilage. (F) DR3ko mice show significantly reduced TRAP+ staining compared with DR3wt mice. *, P < 0.05. (G and H) Representative images of F4/80 staining from DR3wt (G) and DR3ko (H) mice, 3 d after arthritis induction. (I) Summary of day-3 data. (J and K) Representative images of F4/80 staining from DR3wt (J) and DR3ko (K) mice, 21 d after induction of arthritis. F4/80-positive cells (arrows) are shown. (L) Summary of day-21 data. Each point in the summary graphs represents a single DR3wt (▵) or DR3ko (▪) animal. Bars, 50 μm. One representative experiment of two is shown.
Mentions: Because DR3ko mice were protected from the development of subchondral bone erosions in AIA, we elected to quantify the number of bone-resorbing osteoclasts within the joint at two distinct sites of epiphyseal bone. Osteoclasts are clearly visualized as large red multinucleated cells with tartrate-resistant acid phosphatase (TRAP). TRAP expression in DR3wt and DR3ko mice was comparable in the femoral head (Fig. 3, A–C) and growth plate (not depicted). However, in the periosteum at areas adjacent to pannus formation, where focal bone erosions could be visualized at high magnification, TRAP staining was significantly greater in DR3wt mice than at equivalent areas in DR3ko mice (Fig. 3, D–F). These data implicate a role for DR3 in generation of osteoclasts at sites of bone pathology but not in influencing osteoclastogenesis in areas away from the pannus.

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