A marine fungus‐derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF‐κB ligand‐induced osteoclastogenesis and inflammatory bone destruction

化学 NF-κB 激活剂(遗传学) 炎症 信号转导 细胞生物学 生物化学 受体 免疫学 生物
作者
Yanhui Tan,Wende Deng,Yueyang Zhang,Minhong Ke,Binhua Zou,Xiaowei Luo,Jianbin Su,Yiyuan Wang,Jialan Xu,Kutty Selva Nandakumar,Yonghong Liu,Xuefeng Zhou,Xiaojuan Li
出处
期刊:British Journal of Pharmacology [Wiley]
卷期号:177 (18): 4242-4260 被引量:28
标识
DOI:10.1111/bph.15179
摘要

Osteoclasts are unique cells to absorb bone. Targeting osteoclast differentiation is a therapeutic strategy for osteolytic diseases. Natural marine products have already become important sources of new drugs. The naturally occurring nitrobenzoyl sesquiterpenoids first identified from marine fungi in 1998 are bioactive compounds with a special structure, but their pharmacological functions are largely unknown. Here, we investigated six marine fungus-derived nitrobenzoyl sesquiterpenoids on osteoclastogenesis and elucidated the mechanisms.Compounds were first tested by RANKL-induced NF-κB luciferase activity and osteoclastic TRAP assay, followed by molecular docking to characterize the structure-activity relationship. The effects and mechanisms of the most potent nitrobenzoyl sesquiterpenoid on RANKL-induced osteoclastogenesis and bone resorption were further evaluated in vitro. Micro-CT and histology analysis were used to assess the prevention of bone destruction by nitrobenzoyl sesquiterpenoids in vivo.Nitrobenzoyl sesquiterpenoid 4, with a nitrobenzoyl moiety at C-14 and a hydroxyl group at C-9, was the most active compound on NF-κB activity and osteoclastogenesis. Consequently, nitrobenzoyl sesquiterpenoid 4 exhibited suppression of RANKL-induced osteoclastogenesis and bone resorption from 0.5 μM. It blocked RANKL-induced IκBa phosphorylation, NF-κB p65 and RelB nuclear translocation, NFATc1 activation, reduced DC-STAMP but not c-Fos expression during osteoclastogenesis in vitro. Nitrobenzoyl sesquiterpenoid 4 also ameliorated LPS-induced osteolysis in vivo.These results highlighted nitrobenzoyl sesquiterpenoid 4 as a novel inhibitor of osteoclast differentiation. This marine-derived sesquiterpenoid is a promising lead compound for the treatment of osteolytic diseases.
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