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Abstract
Genistein and icariin are flavonoid compounds that exhibit estrogen-like properties in inducing bone formation and reducing bone loss associated with estrogen deficiency in both preclinical and clinical studies. However, the mechanisms that are involved in mediating their estrogenic actions in bone cells are far from clear. The present study aimed to study the signaling pathways that mediate the estrogenic actions of genistein and icariin in osteoblastic cells. The effects of genistein and icariin on the activation of estrogen receptor (ER) and the downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in murine osteoblastic MC3T3-E1 cells and rat osteoblastic UMR-106 cells were studied. As expected, genistein displayed higher binding affinity toward ERβ than ERα and significantly induced estrogen response element (ERE)-dependent transcription in UMR-106 cells in a dose-dependent manner. In contrast, icariin failed to bind to ERα or ERβ and did not induce ERE-dependent transcription in UMR-106 cells at 10-10 to 10-7 M. The effects of genistein (10 nM) and icariin (0.1 μM) on cell proliferation and differentiation in osteoblastic UMR-106 cells were abolished in the presence of ER antagonist ICI 182,780 (1 μM), MAPK inhibitor U0126 (10 μM), and PI3K inhibitor LY294002 (10 μM). Genistein at 10 nM rapidly induced ERK1/2 phosphorylation at 5–10 min in UMR-106 cells and the phosphorylation of ERα at both Ser118 and Ser167 in both MC3T3-E1 and transfected UMR-106 cells whereas icariin at 0.1 μM rapidly activated both ERK1/2 and Akt phosphorylation in UMR-106 cells and subsequent ERα phosphorylation at both Ser118 and Ser167 in MC3T3-E1 and transfected UMR-106 cells. Confocal imaging studies confirmed that the phosphorylation of ERα at Ser 118 and Ser 167 by genistein and icariin in MC3T3-E1 cells was mediated via MAPK- and PI3K-dependent pathway, respectively. Furthermore, our studies showed that icariin exerted stronger anti-apoptotic effects than genistein and 17β-estradiol (E2) and inhibited the cleavage of downstream caspase-3 in MC3T3-E1 cells induced by a potent PI3K inhibitor, PI828 (at 2 μM). These results indicated that the mechanisms that mediate the estrogenic actions of icariin in osteoblastic cells are different from those of genistein.
Highlights
Concern for the use of hormone replacement therapy (HRT) in increasing postmenopausal women’s risk of breast cancer, stroke, thrombosis, and cardiovascular diseases (Rossouw et al, 2002; Beral and Million Women Study Collaborators, 2003) has triggered research efforts to develop alternative approaches for managing menopausal syndromes and preventing postmenopausal osteoporosis
The results indicated that icariin exerted bone anabolic effects in both types of osteoblastic cells at concentrations as low as 10−12 M while higher concentrations of genistein (10−9–10−6 M) are required to induce anabolic effects in MC3T3-E1 cells
Using pathway-specific blockers, our study showed that the osteogenic effects of genistein (10 nM) and icariin (0.1 μM) at their most effective dosages were estrogen receptor (ER)-dependent and involved the activation of mitogen-activated protein kinase (MAPK)/ERK signaling for cell proliferation and phosphatidylinositol 3-kinase (PI3K)/Akt signaling for cell differentiation
Summary
Concern for the use of hormone replacement therapy (HRT) in increasing postmenopausal women’s risk of breast cancer, stroke, thrombosis, and cardiovascular diseases (Rossouw et al, 2002; Beral and Million Women Study Collaborators, 2003) has triggered research efforts to develop alternative approaches for managing menopausal syndromes and preventing postmenopausal osteoporosis. Phytoestrogens are compounds present in plants with estrogen-like biological activities and different phytoestrogen preparations are popular among postmenopausal women as dietary supplement for management of menopausal symptoms (Lagari and Levis, 2010; Gil-Izquierdo et al, 2012) and they might be useful for management of bone health (Weaver and Cheong, 2005; Poulsen and Kruger, 2008; Zhang et al, 2008a; Lagari and Levis, 2014). Especially soy isoflavones, are by far the most frequently studied phytoestrogens that have been reported (Weaver and Cheong, 2005; Poulsen and Kruger, 2008; Zhang et al, 2008a,b; Lagari and Levis, 2010, 2014). With the recent increase in the number of study and application of diverse types of phytoestrogens, it is of prime importance to understand the mechanism of actions of each type of phytoestrogen for better prediction of their therapeutic profiles and for avoiding their potential adverse side effects upon longterm exposure
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