Protection against Ovariectomy-Induced Bone Loss by Tranilast

Background: Tranilast (N-(3 ',4 '-dimethoxycinnamonyl) anthranilic acid) has been shown to be therapeutically effective, exerting anti-inflammatory and anti-oxidative effects via acting on macrophage. We hypothesized that Tranilast may protect against oxidative stress-induced bone loss via action in osteoclasts (OCs) that shares precursors with macrophage. Methodology and Principal Findings: To elucidate the role of Tranilast, ovariectomy (OVX)-induced bone loss in vivo and OC differentiation in vitro were evaluated by mu CT and tartrate-resistant acid phosphatase staining, respectively. Oral administration of Tranilast protected against OVX-induced bone loss with decreased serum level of reactive oxygen species (ROS) in mice. Tranilast inhibited OC formation in vitro. Decreased osteoclastogenesis by Tranilast was due to a defect of receptor activator of nuclear factor-kappa B ligand (RANKL) signaling, at least partly via decreased activation of nuclear factor-kB and reduced induction and nuclear translocation of nuclear factor of activated T cells, cytoplasmic 1 (or NFAT2). Tranilast also decreased RANKL-induced a long lasting ROS level as well as TGF-beta to inhibit osteoclastogenesis. Reduced ROS caused by Tranilast was due to the induction of ROS scavenging enzymes (peroxiredoxin 1, heme oxygenase-1, and glutathione peroxidase 1) as well as impaired ROS generation. Conclusions/Significance: Our data suggests the therapeutic potential of Tranilast for amelioration of bone loss and oxidative stress due to loss of ovarian function.