Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis.
Finding a means to ameliorate and prevent bone destruction is one of the urgent issues in the treatment of rheumatoid arthritis. Recent studies revealed bone-resorbing osteoclasts to be essential for arthritic bone destruction, but to date there has been scarce experimental evidence for the underlying mechanism of the bone-protective effect of antirheumatic drugs. Here we examined the effects of one or a combination of disease-modifying antirheumatic drugs (DMARDs) on osteoclast differentiation to provide a cellular and molecular basis for their efficacy against bone destruction. The effects on osteoclast precursor cells and osteoclastogenesis-supporting cells were distinguished by two in vitro osteoclast culture systems. Methotrexate (MTX), bucillamine (Buc) and salazosulphapyridine (SASP) inhibited osteoclastogenesis by acting on osteoclast precursor cells and interfering with receptor activator of NF-kappaB ligand (RANKL)-mediated induction of the nuclear factor of activated T cells (NFAT) c1. MTX and SASP also suppressed RANKL expression on osteoclastogenesis-supporting mesenchymal cells. Interestingly, the combination of three antirheumatic drugs exerted a marked inhibitory effect on osteoclastogenesis even at a low dose at which there was much less of an effect when administered individually. These results are consistent with the reported efficacy of combined DMARDs therapy in humans and suggest that osteoclast culture systems are useful tools to provide an experimental basis for the bone-protective effects of antirheumatic drugs.
Suematsu
Ayako
A
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University and COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, 1-5-45 Yushima, Tokyo 113-8549, Japan.
Tajiri
Yasuhito
Y
Nakashima
Tomoki
T
Taka
Junko
J
Ochi
Sae
S
Oda
Hiromi
H
Nakamura
Kozo
K
Tanaka
Sakae
S
Takayanagi
Hiroshi
H
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000188:drug therapy*; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D053245:RANK Ligand / Q000187:drug effects / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology
D018501:Antirheumatic Agents; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D012460:Sulfasalazine; D003545:Cysteine; C026535:bucillamine; D008727:Methotrexate