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 ERα modulators from
crude extracts of several plant endophytes. As a result, NOR purified from the extract of endophyte ARL-13 was identified as a selective ERα modulator. NOR directly bound to ERα with 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 ERα and
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 ERα with substantial anti-
osteoporosis but less estrogenic activity.