title: Wedelolactone enhances osteoblastogenesis by regulating Wnt/β-catenin signaling pathway but suppresses osteoclastogenesis by NF-κB/c-fos/NFATc1 pathway.
abstract: Bone homeostasis is maintained by formation and destruction of bone, which are two processes tightly coupled and controlled. Targeting both stimulation on bone formation and suppression on bone resorption becomes a promising strategy for treating osteoporosis. In this study, we examined the effect of wedelolactone, a natural product from Ecliptae herba, on osteoblastogenesis as well as osteoclastogenesis. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone stimulated osteoblast differentiation and bone mineralization. At the molecular level, wedelolactone directly inhibited GSK3β activity and enhanced the phosphorylation of GSK3β, thereafter stimulated the nuclear translocation of β-catenin and runx2. The expression of osteoblastogenesis-related marker gene including osteorix, osteocalcin and runx2 increased. At the same concentration range, wedelolactone inhibited RANKL-induced preosteoclastic RAW264.7 actin-ring formation and bone resorption pits. Further, wedelolactone blocked NF-kB/p65 phosphorylation and abrogated the NFATc1 nuclear translocation. As a result, osteoclastogenesis-related marker gene expression decreased, including c-src, c-fos, and cathepsin K. In ovariectomized mice, administration of wedelolactone prevented ovariectomy-induced bone loss by enhancing osteoblast activity and inhibiting osteoclast activity. Together, these data demonstrated that wedelolactone facilitated osteoblastogenesis through Wnt/GSK3β/β-catenin signaling pathway and suppressed RANKL-induced osteoclastogenesis through NF-κB/c-fos/NFATc1 pathway. These results suggested that wedelolacone could be a novel dual functional therapeutic agent for osteoporosis.
authors: Academy of Integrative Medicine, Dalian Medical University, Dalian 116044, China.
authors: Yan-Qiu
authors: YQ
authors: Liu
authors: Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Dalian 116023, China.
authors: Zhi-Lai
authors: ZL
authors: Hong
authors: School of Basic Medical Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors: Li-Bin
authors: LB
authors: Zhan
authors: Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Dalian 116023, China.
authors: Hui-Ying
authors: HY
authors: Chu
authors: Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Dalian 116023, China.
authors: Xiao-Zhe
authors: XZ
authors: Zhang
authors: Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Dalian 116023, China.
authors: Guo-Hui
authors: GH
authors: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D003022:Clotrimazole / Q000031:analogs & derivatives; D003374:Coumarins / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D003374:Coumarins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D051176:beta Catenin; C051122:wedelolactone; C076986:flutrimazole; D003022:Clotrimazole