Methotrexate inhibits rheumatoid synovitis by inducing apoptosis.
OBJECTIVE
To clarify the pharmacological action of methotrexate (MTX) on the synovium of patients with rheumatoid arthritis (RA) using severe combined immunodeficient (SCID) mice in which human RA synovial tissue had been grafted (SCID-HuRAg).


METHODS
One month after engraftment of human RA tissue into SCID mice, MTX (0.3 mg/kg) was administered orally, then the appearance of apoptosis in the grafted tissue was examined by TdT mediated dUTP nick end labeling (TUNEL) staining and electron microscopy at various time points after MTX administration. In cultured synovial cells, synovial apoptotic changes after MTX treatment were studied by agarose gel electrophoresis and flow cytometric analysis. To compare the histological changes induced by MTX with those induced by other disease modifying antirheumatic drugs (DMARD) and a nonsteroidal antiinflammatory drug, histological examination of the grafted synovial tissues from SCID-HuRAg mice was conducted after 4 weeks of oral administration of MTX (0.3 mg/kg/week), salazosulfapyridine (30 mg/kg/day), auranofin (0.2 mg/kg/day), bucillamine (10 mg/kg/day), or indomethacin (2 mg/kg/day).


RESULTS
A significant decrease in the number of inflammatory cells was observed in the grafted synovial tissue of MTX treated SCID-HuRAg. A similar antiinflammatory effect was not observed with the other DMARD. Induction of apoptosis was noted with MTX treatment but not with the others. The pro-apoptotic effect of MTX was also observed in synovial cell cultures.


CONCLUSIONS
MTX induces apoptosis in RA synovium that, in turn, may contribute to its antiinflammatory effect on RA synovitis.
Nakazawa
F
F
Department of Orthopedic Surgery, Toyama Medical and Pharmaceutical University, Japan. fujio@ms.toyama-mpu.ac.jp
Matsuno
H
H
Yudoh
K
K
Katayama
R
R
Sawai
T
T
Uzuki
M
M
Kimura
T
T
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D008854:Microscopy, Electron; D013583:Synovial Membrane / Q000473:pathology / Q000637:transplantation / Q000648:ultrastructure; D013585:Synovitis / Q000188:drug therapy* / Q000473:pathology
D018501:Antirheumatic Agents; D008727:Methotrexate