TY - JOUR
T1 - 8-prenylgenistein exerts osteogenic effects via ER α and Wnt-dependent signaling pathway
AU - Qiu, Zuo cheng
AU - Zhang, Yan
AU - Xiao, Hui hui
AU - Poon, Christina Chui-Wa
AU - Li, Xiao li
AU - Cui, Jian fang
AU - Wong, Man kin
AU - Yao, Xin sheng
AU - Wong, Man sau
N1 - Funding Information:
This work was funded by: National Natural Science Foundation of China ( 81903618 , 81220108028 and 81803801 ); the China Postdoctoral Science Foundation ( 2018M640844 ); the Hong Kong Polytechnic University Research support ( 1-BBAB ), China; Shenzhen Basic Research Program ( JCYJ20140819153305696 and JCYJ20151030164008764 ), China; the National Major Scientific and Program of Introducing Talents of Discipline to Universities ( B13038 ), China; the Hundred Talents Program from Shanghai Municipal Commission of Health and Family Planning ( 2018BR03 ), China; Essential Drug Research and Development ( 2019ZX09201004-003-032 ) from Ministry of Science and Technology of China .
Funding Information:
This work was funded by: National Natural Science Foundation of China (81903618, 81220108028 and 81803801); the China Postdoctoral Science Foundation (2018M640844); the Hong Kong Polytechnic University Research support (1-BBAB), China; Shenzhen Basic Research Program (JCYJ20140819153305696 and JCYJ20151030164008764), China; the National Major Scientific and Program of Introducing Talents of Discipline to Universities (B13038), China; the Hundred Talents Program from Shanghai Municipal Commission of Health and Family Planning (2018BR03), China; Essential Drug Research and Development (2019ZX09201004-003-032) from Ministry of Science and Technology of China.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 8-prenylgenistein (8PG) was previously reported to exert stronger osteogenic activity than genistein, a well-known soy phytoestrogen. However, the molecular mechanism underlying the actions of 8PG on osteoblasts was far from clear. In the present study, the osteogenic effects and mechanisms of 8PG and genistein were studied using human BMSC and murine pre-osteoblast MC3T3-E1 cells. Our results indicated that the stimulatory effects of 8PG and genistein on osteoblast differentiation were abolished by co-incubation with MPP (10−6 M, an ERα antagonist), but not PHTPP (10−6 M, an ERβ antagonist). Molecular docking indicated that the binding mode of 8PG toward ERα was similar to that of genistein and therefore could not account for their differential osteogenic actions. In silico target profiling identified the involvement of glycogen synthase kinase-3β (GSK-3β), a key mediator of Wnt/β-catenin pathway, in the actions of 8PG. However, instead of directly inhibiting GSK-3β enzymatic activities, 8PG and genistein were found to induce GSK-3β phosphorylation at Serine-9 in osteoblastic MC3T3-E1 cells. 8PG exerted more potent effects than genistein in stimulating expressions of LRP5, β-catenin, Runx2, osteocalcin, alp, opg, major protein and gene markers involved in Wnt signaling pathway in MC3T3-E1 cells. Moreover, the inhibition of Wnt signaling by DKK1 could be restored by treatment with 8PG and genistein. However, 8PG, but not genistein, stimulated ERα-dependent β-catenin protein expression in MC3T3-E1 cells. Furthermore, the increase in ALP activity, LRP5 and phospho-Akt/Akt expression by 8PG and genistein were abolished by co-treatment with LY294002 (10−5 M, a PI3K pathway inhibitor). Collectively, our results suggested that the osteogenic activities of 8PG was mediated by GSK-3β phosphorylation through the induction of Wnt/β-catenin and ERα-associated PI3K/Akt signaling.
AB - 8-prenylgenistein (8PG) was previously reported to exert stronger osteogenic activity than genistein, a well-known soy phytoestrogen. However, the molecular mechanism underlying the actions of 8PG on osteoblasts was far from clear. In the present study, the osteogenic effects and mechanisms of 8PG and genistein were studied using human BMSC and murine pre-osteoblast MC3T3-E1 cells. Our results indicated that the stimulatory effects of 8PG and genistein on osteoblast differentiation were abolished by co-incubation with MPP (10−6 M, an ERα antagonist), but not PHTPP (10−6 M, an ERβ antagonist). Molecular docking indicated that the binding mode of 8PG toward ERα was similar to that of genistein and therefore could not account for their differential osteogenic actions. In silico target profiling identified the involvement of glycogen synthase kinase-3β (GSK-3β), a key mediator of Wnt/β-catenin pathway, in the actions of 8PG. However, instead of directly inhibiting GSK-3β enzymatic activities, 8PG and genistein were found to induce GSK-3β phosphorylation at Serine-9 in osteoblastic MC3T3-E1 cells. 8PG exerted more potent effects than genistein in stimulating expressions of LRP5, β-catenin, Runx2, osteocalcin, alp, opg, major protein and gene markers involved in Wnt signaling pathway in MC3T3-E1 cells. Moreover, the inhibition of Wnt signaling by DKK1 could be restored by treatment with 8PG and genistein. However, 8PG, but not genistein, stimulated ERα-dependent β-catenin protein expression in MC3T3-E1 cells. Furthermore, the increase in ALP activity, LRP5 and phospho-Akt/Akt expression by 8PG and genistein were abolished by co-treatment with LY294002 (10−5 M, a PI3K pathway inhibitor). Collectively, our results suggested that the osteogenic activities of 8PG was mediated by GSK-3β phosphorylation through the induction of Wnt/β-catenin and ERα-associated PI3K/Akt signaling.
KW - 8-prenylgenistein
KW - Estrogen receptor α
KW - Genistein
KW - GSK-3β
KW - Osteoblast
KW - PI3K/Akt signaling pathway
KW - Wnt/β-catenin signaling pathway
UR - http://www.scopus.com/inward/record.url?scp=85088271836&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2020.112186
DO - 10.1016/j.yexcr.2020.112186
M3 - Journal article
C2 - 32698024
AN - SCOPUS:85088271836
VL - 395
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 1
M1 - 112186
ER -