摘要
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.
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)
the Regional Demonstration of Marine Economy Innovative Development Project(Grant No.16PYY007SF17,China)
the Fujian Provincial Science&Technology Department(Grant No.2017YZ0002-1,China)
作者简介
Corresponding authors:Hu Zhou,Tel.:+865922881105,fax:+865922881105.E-mail addresses:huzhou@xmu.edu.cn;Corresponding authors:Ting Lin,E-mail addresses:linting@xmu.edu.cn
