Open AccessThe antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF‐κB ligand–stimulated induction of nuclear factor of activated T cells c1
Author(s) -
Urushibara Makoto,
Takayanagi Hiroshi,
Koga Takako,
Kim Sunhwa,
Isobe Miho,
Morishita Yasuyuki,
Nakagawa Takumi,
Löeffler Monika,
Kodama Tatsuhiko,
Kurosawa Hisashi,
Taniguchi Tadatsugu
Publication year - 2004
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.20206
Subject(s) - leflunomide , osteoclast , rankl , activator (genetics) , chemistry , cancer research , rank ligand , pharmacology , microbiology and biotechnology , receptor , immunology , medicine , biology , rheumatoid arthritis , biochemistry
Abstract Objective Suppression of bone destruction is required as part of an effective therapeutic strategy for autoimmune arthritis. Although numerous antirheumatic drugs are in clinical use, little is known about whether they inhibit bone destruction by acting on activated T cells or other cell types, such as bone‐resorbing osteoclasts. This study was undertaken to determine whether leflunomide has a direct action on the osteoclast lineage and to gain insights into the molecular basis for the bone‐protective effect of leflunomide. Methods The direct effect of leflunomide on osteoclast differentiation was investigated using an in vitro culture system of bone marrow monocyte/macrophages stimulated with receptor activator of NF‐κB ligand (RANKL) and macrophage colony‐stimulating factor. The molecular mechanism of the inhibition was analyzed by genome‐wide screening. The T cell–independent effect of leflunomide was examined in rag‐2 −/− mice. Results Leflunomide blocked de novo pyrimidine synthesis and RANKL‐induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF‐ATc1) was strongly inhibited. The inhibition of this pathway is central to the action of leflunomide, since the inhibition was overcome by ectopic expression of NF‐ATc1 in the precursor cells. Leflunomide suppressed endotoxin‐induced inflammatory bone destruction even in rag‐2 −/− mice. Conclusion Leflunomide has a direct inhibitory effect on RANKL‐mediated osteoclast differentiation by inhibiting the induction of NF‐ATc1, the master switch regulator for osteoclast differentiation. Our study suggests that the direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect in the amelioration of bone destruction, and that the RANKL‐dependent NF‐ATc1 induction pathway is a promising target for pharmacologic intervention in arthritic bone destruction.