Phytoestrogenic Potential of Resveratrol by Selective Activation of Estrogen Receptor-α in Osteoblast Cells

Abstract

Resveratrol obtained in grape seed and skin is structurally similar to a synthetic estrogen diethylstilbestrol. The endogenous estrogen, 17β-estradiol, induces cellular responses by binding to the estrogen receptor alpha and beta. The bone fracture due to decreased bone mineral density in postmenopausal women is linked to reduced estrogen. The adverse drug reactions of hormone replacement therapy warrant identifying unique natural compounds with ER-subtype specificity to improve bone health. Resveratrol is considered a phytoestrogen; however, its isoform selectivity has not yet been established on osteoblast cell lines. Therefore, in vitro and in silico docking studies were performed to analyze the binding affinity and selectivity of resveratrol towards receptor alpha and β-isoforms. Resveratrol was evaluated for its actions on the proliferation and differentiation in the primary rat calvarial osteoblasts and bone marrow cells. Osteoblasts specifically increased receptor alpha expression in rat calvarial osteoblasts cells; however, there was no effect on receptor beta expression. In silico studies further confirmed receptor alpha isoform specificity. The observed differences in the orientation, interaction pattern, and binding affinity of resveratrol at the active site of receptor alpha and beta are supported by the western blot analysis. The estrogen mimetic action of resveratrol suggests its therapeutic potential as a bone anabolic agent for postmenopausal osteoporosis.

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol

“…Furthermore, the function of this natural substance as a phytoestrogen confirms its significance for bone anabolism, allowing resveratrol to activate estrogen receptor-α, which has been linked to increased osteogenesis [ 196 ]. Moreover, the aforementioned up-regulation of Sirt-1 by resveratrol in association with increased autophagy and decreased apoptosis in osteoblasts can be considered as evidence for the phytoestrogenic effect of resveratrol, since estrogen analogues have recently been shown to have a comparable effect [ 45 , 47 , 197 ].…”

Bioactive Compounds and Their Influence on Postnatal Neurogenesis

“…Another well-known natural compound is resveratrol, present in some plants such as red grapes or red wine, which is recognized for its protective properties against vascular diseases, neurodegenerative conditions, atherosclerosis, oxidative stress, and certain types of tumors, primarily due to its antioxidant effects [112]. Resveratrol acts as a phytoestrogen, and its action is dependent on estrogen receptors (ER) [113]. Membrane-associated ERs have been identified in various brain regions involved in learning and memory, including the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus [114].…”

“…Flavonoids and their derivatives, including 7,8-dihydroxyflavone derivatives, have been proven for their potential neuroprotective possibilities [112][113][114]. Quercetin, a naturally occurring flavonoid classified within the flavonol subfamily, is well-known for its anti-inflammatory properties [115].…”

Resveratrol Analogues as Selective Estrogen Signaling Pathway Modulators: Structure–Activity Relationship

“…Their distribution in aromatic rings in the stilbene scaffold makes it similar in chemical structure to endogenous and synthetic estrogens such as 17β-estradiol (E2) or diethylstilbestrol [ 3 ]. The phytoestrogenic activity of resveratrol was assayed in different in vitro and in vivo models [ 3 ], including estrogen receptor-expressing breast, ovarian and endometrial cancer cells, as well as luciferase reporter gene transfected cells [ 6 , 7 , 8 ]. Although these works brought some, on the first look, conflicting results, it is commonly accepted that resveratrol interacts with estrogen receptors (ERs) and functions as a mixed agonist/antagonist [ 9 , 10 , 11 , 12 ].…”

“…That may significantly change their levels and modulate their central and peripheral actions; their interaction with ERs seems to play a crucial role [ 3 ]. The theoretical basics of their interactions with estrogen receptors were described in works presenting its in silico docking to estrogen receptors [ 6 , 14 ]. The hydroxyl groups are similarly responsible for binding estrogen receptors as though they are crucial for resveratrol’s cytotoxic and antioxidative activity [ 15 ].…”