title: 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.
authors.affiliation: Biomedical Research Laboratories, Sankyo Company, Limited, Tokyo, Japan.
authors.forename: Kimihisa
authors.initials: K
authors.lastname: Ichikawa
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Martin
authors.initials: M
authors.lastname: Fleck
authors.forename: Huangge
authors.initials: H
authors.lastname: Zhang
authors.forename: Limin
authors.initials: L
authors.lastname: Zhao
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: William J
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Robert
authors.initials: R
authors.lastname: Kimberly
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D015533:Transcriptional Activation / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; C505640:Tnfrsf10b protein, mouse