ORIGINAL ARTICLE

Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis

Authors

Ayako Suematsu¹, Yasuhito Tajiri², Tomoki Nakashima¹, Junko Taka1, Sae Ochi³, Hiromi Oda², Kozo Nakamura², Sakae Tanaka² and Hiroshi Takayanagi¹

1. 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, Bunkyo-ku, Tokyo 113-8549, Japan
2. Department of Orthopaedic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
3. Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan
4. Solution-Oriented Research for Science and Technology (SORST), Japan Science and Technology Agency (JST), Kawaguchi, Japan

Received:

13 October 2006

Accepted:

18 October 2006

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Abstract

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-κB 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.

Key words

Disease-modifying antirheumatic drugs (DMARDs) - Nuclear factor of activated T cells (NFAT) c1 - Osteoclast - Receptor activator of NF-κB ligand (RANKL) - Rheumatoid arthritis (RA)