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 arthriti

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

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). DR3ko 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 DR3ko 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 diseas