Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
| dc.contributor.advisor | Wong, Man-sau (ABCT) | en_US |
| dc.creator | Wong, Ka Ying | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/10650 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | The involvement of novel estrogen receptors in mediating rapid estrogenic effects of Er-xian decoction and icariin in bone | en_US |
| dcterms.abstract | The estrogen-like bone protective effects of Er-xian decoction (EXD), a Traditional Chinese medicine (TCM) formula, and its abundant flavonoid, icariin, in postmenopausal women have been widely studied; such effects involve the activation of rapid estrogen signaling in osteoblast. Our previous study revealed no binding affinity of icariin to classical estrogen receptors α (ER-α or now called ER-α66) and the involvement of ligand-independent rapid estrogen signaling in mediating the actions of icariin. These suggested that ER-α66 might not be the sole estrogen receptors (ERs) responsible for the estrogenic actions of icariin and icariincontaining EXD. Recently, two novel membrane ERs, estrogen receptor α36 (ER-α36) and G-protein coupled estrogen receptor (GPER), were discovered and reported to mainly mediate rapid estrogen signaling through physical and functional interaction with ER-α66 in estrogen-sensitive tissues. Few studies also found their expressions correlated with bone remodelling. Thus, we hypothesized that ER-α36 and GPER might be the therapeutic targets of icariin and EXD to mediate rapid estrogenic effects through crosstalk with ER-α66 in osteoblasts. In the present study, we first determined that ER-α36 and ER-α66 expression were differentially regulated while ER-α36 and GPER expression were similarly regulated by 17βestradiol (E2) and icariin in osteoblasts. Also, the regulation of ER-α36 expression by E2 or icariin was GPER-dependent and ER-α66-independent. These results provided new insights regarding the regulation of GPER, ER-α36, and ER-α66 expression in osteoblasts and their differential responses to E2 and icariin. Next, we investigated the role of ER-α36 and GPER in the bone protection using transient transfection or GPER specific blockers. Results demonstrated the negative roles of ER-α36 and GPER in ER-α66-mediated estrogenic bone formation induced by icariin in preosteoblast and osteoblast. Such effects are perhaps via translocation from cytoplasm to cell membrane and regulation of ER-α66/ER-α36 and ER-α66/c-src complexes in ERK and Akt rapid estrogen signaling. These results not only indicated the differential activation of ERs by icariin and E2 in bone, but also the negative regulation of bone formation by ER-α36 or GPER and signaling pathway aroused by icariin or E2. As for EXD study, the in vivo study confirmed our previous findings that EXD could exert estrogen-like bone protection without inducing uterotrophic effects in mature female Sprague Dawley OVX rats. EXD also appeared to regulate the ER-α36 or GPER protein expression in tibia heads of rats, indicating the recruitment of these novel ERs in bone by EXD. Our in vitro study futher studied the roles of ER-α36 or GPER in estrogen-like effect of EXD in bone. Results clearly demonstrated that the expression of ER-α36, GPER and ER-α66 were differentially regulated in preosteoblast and osteoblast, suggesting the negative regulation of ER-α36 or GPER in bone formation and rapid estrogen signaling pathway in response to EXD. The last part of the present study focused on examining the involvements of ER-α36 and GPER in bone protection of EXD or icariin in female osteoblast-specific ER-α knockout mice. The study was designed to address the difficulties in distinguishing the role of different ER-α isoforms in mediating the rapid estrogen responses in normal osteoblastic cells. The results might indicate icariin and EXD could exert both ER-α66-dependent and ER-α66-independent bone protective effects in osteoblastic cells. Icariin and EXD might require ER-α66 in regulating E2-senstive bone marker expression, but bypass ER-α66 in promoting cell proliferation of osteoblast cells. Specifically, the rapid estrogen signaling might be preferentially mediated by ER-α36 and GPER over ER-α66 in osteoblast upon treatment of icariin and postmenopausal level of estrogen, presumably as a negative feedback to the actions of ER-α66. In summary, our study provided new insights to extend our understandings of the mechanisms behind the bone protection of icariin and EXD suggesting ER-α36 and GPER might be the target receptors in mediating rapid estrogen signaling. | en_US |
| dcterms.extent | 198 pages : color illustrations | en_US |
| dcterms.issued | 2020 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.LCSH | Estrogen -- Receptors | en_US |
| dcterms.LCSH | Osteoclasts | en_US |
| dcterms.LCSH | Bone cells | en_US |
| dcterms.LCSH | Hong Kong Polytechnic University -- Dissertations | en_US |
| dcterms.accessRights | open access | en_US |
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