The bone-protective effect of the phytoestrogen genistein is mediated via ERα-dependent mechanisms and strongly enhanced by physical activity

Hertrampf, Torsten; Gruca, Marta; Seibel, Jan; Laudenbach, U.; Fritzemeier, Karl Heinrich; Diel, Patrick

doi:10.1016/j.bone.2007.02.006

Cited by 73 publications

(67 citation statements)

References 44 publications

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“…In line with previous findings from our laboratory, our data shows that OVX rats display a stronger increase of body weight compared to E 2 and SHAM rats mainly due to an increase in the percentage of total body fat (Lindberg et al 2001a, Hertrampf et al 2007). In contrast to treatment with 8-VE2, application of 16-LE2 resulted in an antagonization of body weight increase after OVX (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…For example, treatment with the respective compounds affected uterine wet weight in accordance with published literature (Pelzer et al 2005, Hertrampf et al 2007). 16-LE2 stimulated uterine wet weights in a comparable manner to E 2 (Fig.2 A) (Hegele-Hartung et al 2004) whereas treatment with 8-VE2 did not result in a significant stimulation of the uterine wet weight (Hillisch et al 2004).…”

Section: Discussionsupporting

confidence: 87%

“…According to previous findings from our laboratory, treatment with 16-LE2, E 2 but not 8-VE2 resulted in a significant increase of trabecular BMD compared to OVX animals ( Fig.2 C), an effect that can be antagonized by the pure antiestrogen Fas (Hertrampf et al 2007). These data are in agreement with studies performed in knockout mice: application of E 2 did not prevent the development of osteoporosis in ERKO female (Lindberg et al 2001a, Lindberg et al 2002a) and male mice (Lindberg et al 2002b), indicating that the bone-protective effects of E 2 are primarily mediated by ER.…”

Section: Discussionsupporting

confidence: 77%

“…This is in agreement with studies using male and female ER knockout mice (ERKO). In these animals A c c e p t e d M a n u s c r i p t of body weight and composition in wild type animals with natural ratios of both ER subtypes is also mainly mediated via ER (Fig.2 B) (Lindberg et al 2001a, Hertrampf et al 2007). …”

Section: Discussionmentioning

confidence: 94%

“…Moreover, it has to be taken into consideration that skeletal effects of estrogen are not only mediated by classical but also by non- A c c e p t e d M a n u s c r i p t 7 classical ER pathways (Syed et al 2005). Although bone cells express both ER subtypes, in vitro studies (Zaman et al 2000) and those conducted in vivo with ER knockout mice (Windahl et al 1999, Lee et al 2003 or ER subtype-specific ligands (Hertrampf et al 2007) have shown that ERα but not ERβ is required for boneprotection by estrogens.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor subtype-specific effects on markers of bone homeostasis

Hertrampf

Schleipen

Velders

et al. 2008

Molecular and Cellular Endocrinology

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Please cite this article as: Hertrampf, T., Schleipen, B., Velders, M., Laudenbach, U., Fritzemeier, K.H., Diel, P., Estrogen receptor subtype-specific effects on markers of bone homeostasis, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractTo further elucidate the processes involved in the physiology of bone-protection by estrogens, ovariectomized (OVX) rats were treated subcutaneously with 17-estradiol, the ER-specific agonist (16-LE2) and the ER-specific agonist (8-VE2).OVX and intact animals served as controls. Biomarkers of bone-formation (osteocalcin (OC), osteopontin (OPN)) and bone-resorption (telopeptides of collagen type I (CTx), pyridinoline cross-links (Pyd)) were quantified. Bone mineral density was measured by computed tomography.OVX-induced bone loss could be antagonized by subcutaneous administration of 17-estradiol and 16-LE2. Serum levels of CTx, OC and OPN were significantly elevated in OVX compared to intact animals and reduced by 17-estradiol and 16-LE2. Treatment of OVX rats with 8-VE2 did not affect BMD or bone-marker serum levels.Taken together, the complex expression pattern of bone-markers in OVX rats following subcutaneous administration of ER subtype-specific agonists indicates that 17-estradiol exerts its bone-protective effects by modulating the activity of osteoclasts and osteoblasts via ERα.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Hertrampf

Schleipen

Velders

et al. 2008

Molecular and Cellular Endocrinology

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Insights into the antiosteoporotic mechanism of the soy‐derived isoflavone genistein: Modulation of the Wnt/beta‐catenin signaling

Mannino,

Imbesi,

Irrera

et al. 2023

BioFactors

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Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/β‐catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid‐induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy‐derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO‐A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 μM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/β‐catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/β‐catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and β. These data suggest that genistein could induce bone remodeling through Wnt/β‐catenin pathway activation.

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Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling

Ming

Chen

2012

Journal Cellular Physiology

199

138

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Increasingly natural products particularly flavonoids are being explored for their therapeutic potentials in reducing bone loss and maintaining bone health. This study has reviewed previous studies on the two better known flavonoids, genistein and icariin, their structures, functions, action mechanisms, relative potency, and potential application in regulating bone remodeling and preventing bone loss. Genistein, an isoflavone abundant in soy, has dual functions on bone cells, able to inhibit bone resorption activity of osteoclasts and stimulate osteogenic differentiation and maturation of bone marrow stromal progenitor cells (BMSCs) and osteoblasts. Genistein is an estrogen receptor (ER)-selective binding phytoestrogen, with a greater affinity to ERβ. Genistein inhibits tyrosine kinases and inhibits DNA topoisomerases I and II, and may act as an antioxidant. Genistein enhances osteoblastic differentiation and maturation by activation of ER, p38MAPK-Runx2, and NO/cGMP pathways, and it inhibits osteoclast formation and bone resorption through inducing osteoclastogenic inhibitor osteoprotegerin (OPG) and blocking NF-κB signaling. Icariin, a prenylated flavonol glycoside isolated from Epimedium herb, stimulates osteogenic differentiation of BMSCs and inhibits bone resorption activity of osteoclasts. Icariin, whose metabolites include icariside I, icariside II, icaritin, and desmethylicaritin, has no estrogenic activity. However, icariin is more potent than genistein in promoting osteogenic differentiation and maturation of osteoblasts. The existence of a prenyl group on C-8 of icariin molecular structure has been suggested to be the reason why icariin is more potent than genistein in osteogenic activity. Thus, the prenylflavonoids may represent a class of flavonoids with a higher osteogenic activity.

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The bone-protective effect of the phytoestrogen genistein is mediated via ERα-dependent mechanisms and strongly enhanced by physical activity

Cited by 73 publications

References 44 publications

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Insights into the antiosteoporotic mechanism of the soy‐derived isoflavone genistein: Modulation of the Wnt/beta‐catenin signaling

Functions and action mechanisms of flavonoids genistein and icariin in regulating bone remodeling

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