Resveratrol prevents osteoporosis by upregulating FoxO1 transcriptional activity

Abstract

Resveratrol (3,5,4-trihydroxystilbene, RES), a natural antioxidant, prevents bone loss by attenuating damage caused by oxidative stress. Our previous research revealed that the forkhead box O1 (FoxO1)/β-catenin signaling pathway affected the proliferation and differentiation of osteoblasts through its regulation of redox balance, and RES regulated the expression of FoxO1 to control white adipose tissue and then ameliorate an overweight condition. Based on previous research, we hypothesized that RES regulates FoxO1 transcriptional activity through the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway to achieve an antioxidative effect on osteoporosis and then we confirmed this hypothesis in the present study. An ovariectomized (OVX) rat model of osteoporosis and a H2O2-induced oxidative cell injury model in RAW 264.7 cells were established to explore the underlying molecular mechanisms of how RES confers an antioxidant effect and prevents bone loss. The obtained results demonstrated that RES strongly prevented bone loss induced by oxidative stress in vivo. More specifically, RES effectively decreased the receptor activator of nuclear factor-κB ligand (RANKL) together with the tartrate-resistant acid phosphatase-5b (TRAP-5b) level, but elevated the osteoproprotegrin (OPG) level and attenuated bone microarchitecture damage. Notably, RES, due to its antioxidant effect, suppressed RANKL production and then inhibited osteoclastogenesis in the OVX rats. In vitro, RES improved the oxidative stress status of cells and thus inhibited the mRNA expression of osteoclast-specific enzymes. These data indicate that RES has a significant bone protective effect by antagonizing oxidative stress to suppress osteoclast activity, function and formation both in vivo and in vitro. Moreover, at the molecular level, we confirmed, for the first time, that RES upregulated FoxO1 transcriptional activity by inhibiting the PI3K/AKT signaling pathway, and hence promoted resistance to oxidative damage and restrained osteoclastogenesis. Inhibition of the PI3K/AKT signaling pathway may be induced by RANKL. FoxO1 is a major action target of RES to confer anti-osteoporosis function, and whose effect stems from its power to improve redox balance.

<p>Resveratrol Exerts Anti-Osteoarthritic Effect by Inhibiting TLR4/NF-κB Signaling Pathway via the TLR4/Akt/FoxO1 Axis in IL-1β-Stimulated SW1353 Cells</p>

“…It has been reported that resveratrol promoted wound healing in diabetic 47 or increased glycolysis 48 by inhibiting FoxO1. However, the opposite results have also been reported which showed that resveratrol upregulated FoxO1 transcriptional activity in preventing osteoporosis 49 or regulating oxidative stress and apoptosis of renal. 50 In the present study, we found that either resveratrol or IL-1β treatment could activate PI3K/Akt signaling and inactivate FoxO1 in a time-dependent manner in SW1353 cells.…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…Previous studies have indicated the beneficial effects of sirtuins as the best small molecule that activate sirtuins, which extended lifespan in a yeast model [104][105][106][107][108][109]. Although only the longevity extension effect of resveratrol has been reported in C. elegans and D. melanogaster, many subsequent studies reported that resveratrol intake promotes health and plays a preventive role in age-related diseases, such as cancer [110][111][112][113], atherosclerosis [114,115], arthritis [116,117], cataract [118][119][120], cardiovascular disease [121], hypertension [122,123], type 2 diabetes [124][125][126][127], osteoporosis [128][129][130], and Alzheimer disease [131][132][133]. In clinical studies, resveratrol intake improved the memory capacity of elderly individuals and reduced blood lipid levels in obese and type 2 diabetic patients [134,135].…”

Protective effect of resveratrol on estrogen deficiency-induced osteoporosis though attenuating NADPH oxidase 4/nuclear factor kappa B pathway by increasing miR-92b-3p expression

“… 9 – 12 RES could effectively prevent bone loss, as indicated by the in vitro experiments in rats, which lost bone mass due to lack of physical activity and estrogen deficiency. 13 RES inhibits the synthesis of reactive oxygen species, resulting in an increase in the alkaline phosphatase levels and proline hydroxylase activity in MC3 T3-E1 cells and prevention of the differentiation of RAW264.7 cells into osteoclasts. 14 , 15 However, the mechanism of action of RES remains unclear and needs further analysis.…”