TRAIL-R2 (DR5) Mediates Apoptosis of Synovial Fibroblasts in Rheumatoid Arthritis

Abstract

TRAIL has been proposed as an anti-inflammatory cytokine in animal models of rheumatoid arthritis (RA). Using two agonistic mAbs specific for TRAIL-R1 (DR4) and TRAIL-R2 (DR5), we examined the expression and function of these death receptors in RA synovial fibroblast cells. The synovial tissues and primary synovial fibroblast cells isolated from patients with RA, but not those isolated from patients with osteoarthritis, selectively expressed high levels of cell surface DR5 and were highly susceptible to anti-DR5 Ab (TRA-8)-mediated apoptosis. In contrast, RA synoviocytes did not show increased expression of TRAIL-R1 (DR4), nor was there any difference in expression of Fas between RA and osteoarthritis synovial cells. In vitro TRA-8 induced apoptosis of RA synovial cells and inhibited production of matrix metalloproteinases induced by pro-inflammatory cytokines. In vivo TRA-8 effectively inhibited hypercellularity of a SV40-transformed RA synovial cell line and completely prevented bone erosion and cartilage destruction induced by these cells. These results indicate that increased DR5 expression and susceptibility to DR5-mediated apoptosis are characteristic of the proliferating synovial cells in RA. As highly proliferative transformed-appearing RA synovial cells play a crucial role in bone erosion and cartilage destruction in RA, the specific targeting of DR5 on RA synovial cells with an agonistic anti-DR5 Ab may be a potential therapy for RA.

Rheumatoid arthritis synovial fluid fibroblasts express TRAIL‐R2 (DR5) that is functionally active

“…This is consistent with previously reported results by Ichikawa et al, who additionally showed that an anti-DR5 mAb prevents erosive arthritis in a murine xenograft model for human RA (8). Importantly, the anti-DR5 antibody developed by Ichikawa et al does not seem to be hepatotoxic (8,12) and is therefore a good substitute for soluble TRAIL therapy, which induces apoptosis in normal human hepatocytes (11).…”

“…OPG, which is 1 of the 5 known TRAIL receptors, inhibits osteoclastogenesis by binding to RANK ligand and increases bone density in vivo (18). Soluble TRAIL has been described to block the antiosteoclastogenic activity of OPG in vitro (7); this suggests that administration of soluble TRAIL has the potential to accelerate osteoporosis in RA patients (8).…”

“…TRAIL-R3, TRAIL-R4, and OPG act as decoy receptors to block TRAIL-mediated apoptosis, and their level of expression may influence susceptibility to the cytotoxic effects of TRAIL (6). Although normal tissues do not express detectable TRAIL-R2 at the protein level, most cancerous tissues express high levels of TRAIL-R2 (5,8). It has recently been reported that RA synovial tissue and fibroblasts express high levels of DR5 (TRAIL-R2) and are highly susceptible to DR5-mediated apoptosis (8).…”

“…Although normal tissues do not express detectable TRAIL-R2 at the protein level, most cancerous tissues express high levels of TRAIL-R2 (5,8). It has recently been reported that RA synovial tissue and fibroblasts express high levels of DR5 (TRAIL-R2) and are highly susceptible to DR5-mediated apoptosis (8). This appears to be a selective marker for RA synovial cells, since osteoarthritis (OA) synovial cells do not express DR5 and are resistant to DR5-mediated apoptosis (8).…”

“…Administration of TRAIL in humans has raised concerns with regard to the outcome, such as the potential for hepatotoxicity (11) and unpredictable effects that would depend on the expression levels of different TRAIL receptors (6)(7)(8). An agonistic anti-DR5 mAb that induces apoptosis of DR5-bearing cells, while sparing normal human hepatocytes, is a potential therapeutic tool in RA (8,12).…”