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Nobiletin, a NF‐κB signaling antagonist, promotes BMP‐induced bone formation

The NF‐κB family of transcription factors plays an important role in skeletal development and bone homeostasis. In osteoblast cells, NF‐κB signaling has been shown to suppress survival, proliferation, and differentiation. Furthermore, pharmacological suppression of NF‐κB enhances osteoblast differen...

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Detalles Bibliográficos
Autores principales: Rojasawasthien, Thira, Usui, Michihiko, Addison, William N., Matsubara, Takuma, Shirakawa, Tomohiko, Tsujisawa, Toshiyuki, Nakashima, Keisuke, Kokabu, Shoichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927861/
https://www.ncbi.nlm.nih.gov/pubmed/36816515
http://dx.doi.org/10.1096/fba.2022-00093
Descripción
Sumario:The NF‐κB family of transcription factors plays an important role in skeletal development and bone homeostasis. In osteoblast cells, NF‐κB signaling has been shown to suppress survival, proliferation, and differentiation. Furthermore, pharmacological suppression of NF‐κB enhances osteoblast differentiation and bone formation. Thus, NF‐κB antagonists are promising candidates as anabolic agents for enhancing bone mass. In this study, we describe the mechanism by which nobiletin, an inhibitor of NF‐κB activity, regulates osteoblast differentiation and mineralization. We found that in MC3T3‐E1 osteoblast cells, nobiletin inhibited a TNF‐α responsive NF‐κB luciferase reporter and also decreased the induction of classical NF‐κB target genes by TNF‐α. Consistent with this, nobiletin prevented TNF‐α ‐mediated suppression of osteogenesis and potently enhanced the differentiation and mineralization of MC3T3‐E1 cells. Likewise, in an in vivo BMP2‐induced ectopic bone formation assay, nobiletin markedly enhanced ossicle bone volume. Western blotting and SMAD‐responsive luciferase assays also demonstrated that NF‐κB suppression of BMP signaling could be inhibited by nobiletin. Thus, our data suggest that mechanistically, nobiletin prevents the endogenous repression of BMP signaling by TNF‐α, thereby enhancing osteoblast activity. In conclusion, nobiletin is a novel NF‐κB antagonist that may be a useful anabolic agent for bone formation.