Abstract
Summary The present investigation found that curculigoside (CUR) can prevent excess-iron-induced bone loss in mice and cells through antioxidation and inhibiting excess-iron-induced phosphorylation of the Akt-FoxO1 pathway. CUR can attenuate the decreasing of cell viability, enhance autophagy, potentiate the antioxidant effect, and reduce apoptosis in MC3T3-E1 cells treated with excess iron through regulating the expression of FoxO1 target gene. Introduction Oxidative stress induced by iron overload is an important factor involved in primary osteoporosis disease and iron overload-related diseases. Curculigoside (CUR), a phenolic glycoside found abundantly in Curculigo orchioides Gaertn., has been demonstrated to possess antioxidant and antiosteoporotic properties. The aim of the present study is to explore the underlying molecular mechanism of CUR on excess-iron-induced bone loss in mice and osteoblastic MC3T3-E1 cells. Methods An iron-overload mice model was used to study the protective effects of CUR on bone loss induced by oxidative stress. Serum bone metabolism markers and antioxidant enzymes were also measured. To explore the antioxidant mechanism of CUR, the MC3T3-E1 osteoblastic cell line was used. Results In vivo studies showed that BMD and microarchitectural parameters were improved after a 3-month administration of CUR. CUR improved the biochemical parameters related to bone metabolism and the expressions of Runx2, OCN, and type 1 collagen and increased the formation of bone-mineralized nodules in vitro. CUR also inhibited ROS generation and increased the activities of antioxidant enzymes both in vivo and in vitro treated with excess iron. CUR can upregulate the level of FoxO1 and Nrf2, downregulate the level of p53 and the phosphorylation level of FoxO1, improve nuclear translocation of FoxO1, probably by inhibiting the IGFR/AKT signaling pathway, then increased cell viability and autophagy, and reduced apoptosis of MC3T3-E1 cells treated with excess iron by regulating the expression of FoxO1 target genes MnSOD, Gadd45a, Bim, FasL, and Rab7. Conclusions These results demonstrated that CUR was able to alleviate bone loss induced by oxidative stress resulting from iron overload, suggesting its potential use for the treatment of primary osteoporosis and bone loss in iron-overload-related diseases.
Highlights
Osteoporosis is a chronic disease caused by many factors, characterized by bone mass decline and trabecular architecture deterioration leading to an increased risk of fracture
Our previous study found that CUR could increase osteoblastic proliferation, differentiation, and calcification of mouse osteoblastic MC3T3-E1 cells [9], and attenuate dysfunction and oxidative damage induced by hydrogen peroxide in calvarial osteoblasts by decreasing reactive oxygen species (ROS) production and lipid peroxidation and increasing the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) in H2O2-induced osteoblast impairment [10]
The results of bone tissue morphological parameters showed that excess iron resulted in a significant decrease in BVF, trabecular number, and thickness, with a concomitant increase in bone surface to bone volume (BS/BV) and trabecular spacing, while CUR (100 mg/kg) and NAC (500 mg/kg) treatment alleviated the morphological alteration of bone induced by iron excess in mice
Summary
Osteoporosis is a chronic disease caused by many factors, characterized by bone mass decline and trabecular architecture deterioration leading to an increased risk of fracture Both estrogen deficiency and aging can induce oxidative stress, increasing the generation of reactive oxygen species (ROS), decreasing osteoblastic bone formation, and Oxidative Medicine and Cellular Longevity elevating the level of osteoclastic bone resorption [1, 2]. Oral administration of CUR significantly enhanced learning performance and ameliorated bone loss in APP/PS1mutated transgenic mice through decreasing the ROS level and increasing the capacity of antioxidative enzymes [11] These findings demonstrated that the bone-protective effect of CUR may be associated with its antioxidative activity.
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