Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways.
Receptor activator of NF-κB ligand (RANKL) plays critical role in osteoclastogenesis. Targeting RANKL signaling pathways has been a promising strategy for treating osteoclast related bone diseases such as osteoporosis and aseptic prosthetic loosening. Schisantherin A (SA), a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra sphenanthera, has been used as an antitussive, tonic, and sedative agent, but its effect on osteoclasts has been hitherto unknown. In the present study, SA was found to inhibit RANKL-induced osteoclast formation and bone resorption. The osteoclastic specific marker genes induced by RANKL including c-Src, SA inhibited OSCAR, cathepsin K and TRAP in a dose dependent manner. Further signal transduction studies revealed that SA down-regulate RANKL-induced nuclear factor-kappaB (NF-κB) signaling activation by suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the NF-κB transcriptional activity. Moreover, SA also decreased the RANKL-induced MAPKs signaling pathway, including JNK and ERK1/2 posphorylation while had no obvious effects on p38 activation. Finally, SA suppressed the NF-κB and MAPKs subsequent gene expression of NFATc1 and c-Fos. In vivo studies, SA inhibited osteoclast function and exhibited bone protection effect in wear-particle-induced bone erosion model. Taken together, SA could attenuate osteoclast formation and wear particle-induced osteolysis by mediating RANKL signaling pathways. These data indicated that SA is a promising therapeutic natural compound for the treatment of osteoclast-related prosthesis loosening.
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
Yi
Y
He
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
Qing
Q
Zhang
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
Yi
Y
Shen
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
Xia
X
Chen
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China.
Feng
F
Zhou
Department of Orthopaedics, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Changsha, Hunan 410011, PR China. Electronic address: xyeypd@163.com.
Dan
D
Peng
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D034242:Cyclooctanes / Q000494:pharmacology* / Q000627:therapeutic use; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000473:pathology; D010014:Osteolysis / Q000517:prevention & control*; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D053245:RANK Ligand; C034557:schizandrer A
Osteoclasts; Osteolysis; RANKL; Schisantherin A