Amlexanox Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss.
The activity of protein kinases IKK-ε and TANK-binding kinase 1 (TBK1) has been shown to be associated with inflammatory diseases. As an inhibitor of IKK-ε and TBK1, amlexanox is an anti-inflammatory, anti-allergic, immunomodulator and used for treatment of ulcer, allergic rhinitis and asthma in clinic. We hypothesized that amlexanox may be used for treatment of osteoclast-related diseases which frequently associated with a low grade of systemic inflammation. In this study, we investigated the effects of amlexanox on RANKL-induced osteoclastogenesis in vitro and ovariectomy-mediated bone loss in vivo. In primary bone marrow derived macrophages (BMMs), amlexanox inhibited osteoclast formation and bone resorption. At the molecular level, amlexanox suppressed RANKL-induced activation of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPKs), c-Fos and NFATc1. Amlexanox decreased the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. Moreover, amlexanox enhanced osteoblast differentiation of BMSCs. In ovariectomized (OVX) mouse model, amlexanox prevented OVX-induced bone loss by suppressing osteoclast activity. Taken together, our results demonstrate that amlexanox suppresses osteoclastogenesis and prevents OVX-induced bone loss. Therefore, amlexanox may be considered as a new therapeutic candidate for osteoclast-related diseases, such as osteoporosis and rheumatoid arthritis.
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Yong
Y
Zhang
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Hanfeng
H
Guan
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Jing
J
Li
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Zhong
Z
Fang
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Wenjian
W
Chen
From the Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, P.R.China.
Feng
F
Li
D000631:Aminopyridines / Q000008:administration & dosage*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D010024:Osteoporosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D010052:Ovariectomy; D016896:Treatment Outcome
D000631:Aminopyridines; D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D016207:Cytokines; C045742:amlexanox