Suppression of osteoclastogenesis in rheumatoid arthritis by induction of apoptosis in activated CD4+ T cells.
OBJECTIVE
To examine the suppressive effect of anti-human Fas monoclonal antibody (mAb) on osteoclastogenesis in rheumatoid arthritis (RA) both in vitro and in vivo.


METHODS
For in vitro analysis, activated CD4+ T cells derived from peripheral blood mononuclear cells were left untreated or were treated with humanized anti-human Fas mAb (R-125224) and cocultured with human monocytes. On day 12, the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells was counted. For in vivo analysis, tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID-HuRAg-pit model). R-125224 was administered intravenously once a week for 3 weeks. The implanted tissue and dentin slice were removed, and the pits formed on the dentin slice were analyzed.


RESULTS
In vitro, coculture of activated CD4+ T cells and peripheral monocytes induced osteoclastogenesis. The number of TRAP-positive multinucleated cells was reduced when activated CD4+ T cells were treated with R-125224. We established a new animal model for monitoring osteoclastogenesis, SCID-HuRAg-pit. We found that with R-125224 treatment, the number of pits formed on the implanted dentin slices was significantly reduced and the number of lymphocytes in the implanted RA synovial tissue was dramatically reduced in this model.


CONCLUSIONS
This is the first study to demonstrate the suppressive effect of anti-human Fas mAb on osteoclastogenesis in RA synovial tissues through the induction of T cell apoptosis. Induction of apoptosis of infiltrated lymphocytes could be a useful therapeutic strategy for RA, in terms of suppressing both inflammation and bone destruction.
Ogawa
Yukie
Y
Sankyo Co. Ltd., Tokyo, Japan.
Ohtsuki
Masahiko
M
Uzuki
Miwa
M
Sawai
Takashi
T
Onozawa
Yoshiko
Y
Nakayama
Junichi
J
Yonemura
Akiko
A
Kimura
Tomoatsu
T
Matsuno
Hiroaki
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D003804:Dentin / Q000473:pathology / Q000637:transplantation; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology; D013583:Synovial Membrane / Q000473:pathology; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D019014:fas Receptor