Abstract
BackgroundTranilast (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 FindingsTo elucidate the role of Tranilast, ovariectomy (OVX)-induced bone loss in vivo and OC differentiation in vitro were evaluated by µCT 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-κB ligand (RANKL) signaling, at least partly via decreased activation of nuclear factor-κB 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-β 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/SignificanceOur data suggests the therapeutic potential of Tranilast for amelioration of bone loss and oxidative stress due to loss of ovarian function.
Highlights
Postmenopuasal osteoporosis has been attributed to loss of ovarian function, which leads to bone loss through increased bone resorption over bone formation
During osteoclastogenesis two molecules which are generated from bone marrow mesenchymal cells are essential: macrophagecolony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL), a member of the tumor necrosis factor (TNF) family [4]
Tranilast Protects against OVX-induced Bone Loss in vivo To examine the effect of Tranilast on OVX-induced bone loss, we analyzed Micro CT (mCT) of femurs from OVX mice treated with Tranilast or vehicle, and compared the effects with those of sham surgery
Summary
Postmenopuasal osteoporosis has been attributed to loss of ovarian function, which leads to bone loss through increased bone resorption over bone formation. OCs are multinucleated giant cells responsible for bone resorption, differentiate from hematopoietic cells of monocyte/macrophage lineage, and share some morphological and functional properties with macrophages. They are responsible for physiological bone remodeling, and for bone destruction associated with chronic inflammatory disease [3]. During osteoclastogenesis two molecules which are generated from bone marrow mesenchymal cells are essential: macrophagecolony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL), a member of the tumor necrosis factor (TNF) family [4]. We hypothesized that Tranilast may protect against oxidative stress-induced bone loss via action in osteoclasts (OCs) that shares precursors with macrophage
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