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8-prenylgenistein exerts osteogenic effects via ER α and Wnt-dependent signaling pathway.
- Source :
-
Experimental cell research [Exp Cell Res] 2020 Oct 01; Vol. 395 (1), pp. 112186. Date of Electronic Publication: 2020 Jul 19. - Publication Year :
- 2020
-
Abstract
- 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 <superscript>-6</superscript>  M, an ERα antagonist), but not PHTPP (10 <superscript>-6</superscript>  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 <superscript>-5</superscript>  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.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Differentiation drug effects
Cell Proliferation drug effects
Genistein metabolism
Genistein pharmacology
Humans
Molecular Docking Simulation methods
Osteoblasts drug effects
Osteoblasts metabolism
Proto-Oncogene Proteins c-akt metabolism
Estrogen Receptor alpha drug effects
Genistein analogs & derivatives
Osteogenesis drug effects
Wnt Signaling Pathway drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2422
- Volume :
- 395
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Experimental cell research
- Publication Type :
- Academic Journal
- Accession number :
- 32698024
- Full Text :
- https://doi.org/10.1016/j.yexcr.2020.112186