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- Title
Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand-induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca<sup>2+</sup>-nuclear factor of activated T-cells cytoplasmic 1 signaling pathways
- Authors
Wu, Xian; Li, Zhenxi; Yang, Zhengfeng; Zheng, Chunbing; Jing, Ji; Chen, Yihua; Ye, Xiyun; Lian, Xiaoyuan; Qiu, Wenwei; Yang, Fan; Tang, Jie; Xiao, Jianru; Liu, Mingyao; Luo, Jian
- Abstract
Receptor activator of NF-κB ligand (RANKL) stimulation leads to the activation of mitogen-activated protein kinase (MAPK)/AP-1 and Ca2+-nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) signaling pathways in osteoclastogenesis. Targeting these pathways has been an encouraging strategy for bone-related diseases, such as postmenopausal osteoporosis. In this study, we examined the effects of caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) on osteoclastogenesis. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, CADPE suppressed RANKL-induced osteoclast differentiation and actin-ring formation in a dose-dependent manner within non-growth inhibitory concentrations at the early stage, while CADPE had no effect on macrophage colony-stimulating factor (M-CSF)-induced proliferation and differentiation. At the molecular level, CADPE inhibited RANKL-induced phosphorylation of MAPKs, including extracellular signal-regulated kinases 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase (JNK), without significantly affecting the NF-κB signaling pathway. CADPE abrogated RANKL-induced activator protein 1 (AP-1)/FBJ murine osteosarcoma viral oncogene homolog (c-Fos) nuclear translocation and activation. Overexpression of c-Fos prevented the inhibition by CADPE of osteoclast differentiation. Furthermore, CADPE suppressed RANKL-induced the tumor necrosis factor receptor associated factor 6 (TRAF6) interaction with c-src tyrosine kinase (c-Src), blocked RANKL-induced the phosphorylation of protein kinase B (AKT), and inhibited RANKL-induced Ca2+ oscillation. As a result, CADPE decreased osteoclastogenesis-related marker gene expression, including NFATc1, TRAP, cathepsin K, and c-Src. To test the effects of CADPE on osteoclast activity in vivo, we showed that CADPE prevented ovariectomy-induced bone loss by inhibiting osteoclast activity. Together, our data demonstrate that CADPE suppresses osteoclastogenesis and bone loss through inhibiting RANKL-induced MAPKs and Ca2+-NFATc1 signaling pathways. CADPE is a novel agent in the treatment of osteoclast-related diseases, such as osteoporosis. © 2012 American Society for Bone and Mineral Research.
- Subjects
HOMEOSTASIS; BONE injuries; OSTEOCLASTS; OSTEOPOROSIS; PROTEIN kinases
- Publication
Journal of Bone & Mineral Research, 2012, Vol 27, Issue 6, p1298
- ISSN
0884-0431
- Publication type
Article
- DOI
10.1002/jbmr.1576