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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\u2010derived nitrobenzoyl sesquiterpenoids on osteoclastogenesis and elucidated the mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Compounds were first tested by RANKL\u2010induced NF\u2010\u03baB luciferase activity and osteoclastic TRAP assay, followed by molecular docking to characterize the structure\u2013activity relationship. The effects and mechanisms of the most potent nitrobenzoyl sesquiterpenoid on RANKL\u2010induced osteoclastogenesis and bone resorption were further evaluated in vitro. Micro\u2010CT and histology analysis were used to assess the prevention of bone destruction by nitrobenzoyl sesquiterpenoids in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Nitrobenzoyl sesquiterpenoid 4, with a nitrobenzoyl moiety at C\u201014 and a hydroxyl group at C\u20109, was the most active compound on NF\u2010\u03baB activity and osteoclastogenesis. Consequently, nitrobenzoyl sesquiterpenoid 4 exhibited suppression of RANKL\u2010induced osteoclastogenesis and bone resorption from 0.5 \u03bcM. It blocked RANKL\u2010induced I\u03baBa phosphorylation, NF\u2010\u03baB p65 and RelB nuclear translocation, NFATc1 activation, reduced DC\u2010STAMP but not c\u2010Fos expression during osteoclastogenesis in vitro. Nitrobenzoyl sesquiterpenoid 4 also ameliorated LPS\u2010induced osteolysis in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These results highlighted nitrobenzoyl sesquiterpenoid 4 as a novel inhibitor of osteoclast differentiation. This marine\u2010derived sesquiterpenoid is a promising lead compound for the treatment of osteolytic diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15179","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T23:09:46Z","timestamp":1593558586000},"page":"4242-4260","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A marine fungus\u2010derived nitrobenzoyl sesquiterpenoid suppresses receptor activator of NF\u2010\u03baB ligand\u2010induced osteoclastogenesis and inflammatory bone destruction"],"prefix":"10.1111","volume":"177","author":[{"given":"Yanhui","family":"Tan","sequence":"first","affiliation":[{"name":"Laboratory of Anti\u2010inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences Southern Medical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical 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