Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis...Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERαmodulators from crude extracts of several plant endophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERαmodulator.NOR directly bound to ERαwith an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-E1 precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERαand TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERαwith substantial anti-osteoporosis but less estrogenic activity.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.31770811,31471318 and 31271453)the Fundamental Research Funds for the Central Universities(Grant No.20720190082,China)+1 种基金the Regional Demonstration of Marine Economy Innovative Development Project(Grant No.16PYY007SF17,China)the Fujian Provincial Science&Technology Department(Grant No.2017YZ0002-1,China)
文摘Although different types of drugs are available for postmenopausal osteoporosis,the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents.Here,we defined that norlichexanthone(NOR),a natural product,is a ligand of estrogen receptor-alpha(ERα)and revealed its therapeutic potential for postmenopausal osteoporosis.We used mammalian-one hybrid assay to screen for ERαmodulators from crude extracts of several plant endophytes.As a result,NOR purified from the extract of endophyte ARL-13 was identified as a selective ERαmodulator.NOR directly bound to ERαwith an affinity in nanomolar range,revealing that it is a natural ligand of ERα.NOR induced osteoblast formation in MC3T3-E1 precursor cells.Conversely,NOR inhibited receptor activator of nuclear factor-kappa B ligand(RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes.Mechanistically,NOR inhibited RANKL-induced association of ERαand TRAF6 to prevent ERα-mediated TRAF6 activation via Lys63-linked ubiquitination.Importantly,NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model.Comparing to estrogen,NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation.Taken together,our study identified NOR as a natural and high affinity ligand of ERαwith substantial anti-osteoporosis but less estrogenic activity.
