title: Flavonoids from Herba epimedii selectively activate estrogen receptor alpha (ERα) and stimulate ER-dependent osteoblastic functions in UMR-106 cells.
abstract: Total flavonoids in Herba epimedii (HEP) have been demonstrated to protect against bone loss and bone deterioration associated with estrogen deficiency without exerting any uterotrophic effects. However, it is unclear how flavonoids in HEP exert their protective effects on bone and if different flavonoids exert estrogenic actions in bone cells via similar mechanism of actions. The present study aims to investigate the bone anabolic effects of four major flavonoids isolated from HEP, namely icariin, baohuoside-I, epimedin B and sagittatoside A as well as the mechanism involved in mediating their estrogenic actions in rat osteoblastic-like UMR-106 cells. All tested compounds significantly stimulated the cell proliferation rate, alkaline phosphate (ALP) activity and osteoprotegerin (OPG)/receptor activator of nuclear factor κ-B ligand (RANKL) mRNA expression in UMR-106 cells and their effects could be abolished by co-incubation with 10(-6)M ICI 182,780. None of the flavonoids exhibited binding affinities toward ERα and ERβ. However, sagittatoside A selectively activated estrogen response element (ERE)-luciferase activity via ERα. In addition, icariin and sagittatoside A induced ERα phosphorylation at serine 118 residue. Taken together, our results indicated that all four flavonoids from HEP stimulated ER-dependent osteoblastic functions in UMR-106 cells, but only two of them appeared to exert their actions by ligand-independent activation of ERα. Our study provides evidence to support the hypothesis that the estrogen-like protective effects on bone by flavonoids are mediated via mechanisms that are distinct from the classical actions of estrogen.
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of The Hong Kong Polytechnic University, Shenzhen 518057, PR China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Xiao
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
authors.forename: Chung-Yan
authors.initials: CY
authors.lastname: Fung
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
authors.forename: Sao-King
authors.initials: SK
authors.lastname: Mok
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
authors.forename: Ka-Chun
authors.initials: KC
authors.lastname: Wong
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China.
authors.forename: Ming-Xian
authors.initials: MX
authors.lastname: Ho
authors.affiliation: Translational Medicine Research and Development Center, Shenzhen, Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, PR China.
authors.forename: Xin-Luan
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), Shenzhen Research Institute of The Hong Kong Polytechnic University, Shenzhen 518057, PR China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, PR China. Electronic address: bcmswong@polyu.edu.hk.
authors.forename: Man-Sau
authors.initials: MS
authors.lastname: Wong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004224:Diterpenes; D004365:Drugs, Chinese Herbal; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005419:Flavonoids; D005960:Glucosides; D012333:RNA, Messenger; C102248:sagittarioside a; C106053:epimedin B; C060988:baohuoside I; C056599:icariin
keywords: Estrogen receptor; Flavonoids; Herba epimedii; Osteoblastic cells; Phytoestrogens