Activation of FoxO1/SIRT1/RANKL/OPG Pathway May Underlie the Therapeutic Effects of Resveratrol on Aging-dependent Male Osteoporosis

Overview

Journal BMC Musculoskelet Disord

Publisher Biomed Central

Specialties Orthopedics
Physiology

Date 2020 Jun 14

PMID 32532246

Citations 12

Authors

Omnia Ameen

Rania I Yassien

Yahya M Naguib

Affiliations

Soon will be listed here.

Abstract

Background: Age-dependent male osteoporosis remains a poorly studied medical problem despite its significance. It is estimated that at least 1 of 5 men will suffer from osteoporotic consequences. Given that multiple mechanisms are involved in the process of senescence, much attention has been given to compounds with polymodal actions. To challenge such a health problem, we tested here the therapeutic potential of resveratrol in male osteoporosis. We also studied the possible molecular mechanisms that may underlie resveratrol effects.

Methods: Thirty male Wistar albino rats were used in the present study. Rats were divided (10/group) into: control (3-4 months old weighing 150-200 g receiving vehicle), aged (18-20 months old, weighing 350-400 g and receiving vehicle), and resveratrol treated aged (18-20 months old, weighing 350-400 g and receiving resveratrol 20 mg/kg/day for 6 weeks) groups. Assessment of serum calcium, phosphate, bone specific alkaline phosphatase, inflammatory cytokines, oxidative stress markers, and rat femur gene expression of FoxO1, SIRT1, RANKL and OPG proteins was carried out. Histopathological assessment of different levels of rat femur was also performed.

Results: Age-dependent osteoporosis resulted in significant increase in serum levels of phosphate, bone specific alkaline phosphatase, hsCRP, IL-1β, IL-6, TNF-α, MDA, NO, and RANKL gene expression. However, there was significant decrease in serum level of GSH, and gene expression of FoxO1, SIRT1 and OPG. Osteoporotic changes were seen in femur epiphysis, metaphysis and diaphysis. Resveratrol restored significantly age-dependent osteoporotic changes.

Conclusion: We concluded that resveratrol can play an important role in the prevention of male osteoporosis. Resveratrol can counter the molecular changes in male osteoporosis via anti-inflammatory, anti-oxidant and gene modifying effects.

Citing Articles

Role of sirtuins in obesity and osteoporosis: molecular mechanisms and therapeutic targets.

Du Y, Huo Y, Yang Y, Lin P, Liu W, Wang Z Cell Commun Signal. 2025; 23(1):20.

PMID: 39799353 PMC: 11724515. DOI: 10.1186/s12964-024-02025-7.

Promising potential effects of resveratrol on oral and dental health maintenance: a comprehensive review.

Farhad S, Karbalaeihasanesfahani A, Dadgar E, Nasiri K, Hosseini N, Valian N Naunyn Schmiedebergs Arch Pharmacol. 2024; 398(2):1367-1389.

PMID: 39305330 DOI: 10.1007/s00210-024-03457-1.

Sirt1: An Increasingly Interesting Molecule with a Potential Role in Bone Metabolism and Osteoporosis.

Chen Y, Xiao H, Liu Z, Teng F, Yang A, Geng B Biomolecules. 2024; 14(8).

PMID: 39199358 PMC: 11352324. DOI: 10.3390/biom14080970.

Exogenous and endogenous antioxidants in osteoporosis risk: causal associations unveiled by Mendelian Randomization analysis.

Li Y, Qi H, Huang X, Lu G, Pan H Front Physiol. 2024; 15:1411148.

PMID: 38883185 PMC: 11176562. DOI: 10.3389/fphys.2024.1411148.

Exploring epigenetic strategies for the treatment of osteoporosis.

Yi S, Lim J, Kim K Mol Biol Rep. 2024; 51(1):398.

PMID: 38453825 DOI: 10.1007/s11033-024-09353-4.

References

Johnell O, Kanis J . An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006; 17(12):1726-33. DOI: 10.1007/s00198-006-0172-4. View

Petrovski G, Gurusamy N, Das D . Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci. 2011; 1215:22-33. DOI: 10.1111/j.1749-6632.2010.05843.x. View

Motawea S, Noreldin R, Naguib Y . Potential therapeutic effects of endothelial cells trans-differentiated from Wharton's Jelly-derived mesenchymal stem cells on altered vascular functions in aged diabetic rat model. Diabetol Metab Syndr. 2020; 12:40. PMC: 7216374. DOI: 10.1186/s13098-020-00546-y. View

El Agamy D, Naguib Y . CoQ10 ameliorates monosodium glutamate-induced alteration in detrusor activity and responsiveness in rats via anti-inflammatory, anti-oxidant and channel inhibiting mechanisms. BMC Urol. 2019; 19(1):103. PMC: 6819562. DOI: 10.1186/s12894-019-0534-9. View

Wang X, Chen L, Peng W . Protective effects of resveratrol on osteoporosis via activation of the SIRT1-NF-κB signaling pathway in rats. Exp Ther Med. 2017; 14(5):5032-5038. PMC: 5704326. DOI: 10.3892/etm.2017.5147. View

Fontani F, Marcucci G, Iantomasi T, Brandi M, Vincenzini M . Glutathione, N-acetylcysteine and lipoic acid down-regulate starvation-induced apoptosis, RANKL/OPG ratio and sclerostin in osteocytes: involvement of JNK and ERK1/2 signalling. Calcif Tissue Int. 2015; 96(4):335-46. DOI: 10.1007/s00223-015-9961-0. View

Rached M, Kode A, Xu L, Yoshikawa Y, Paik J, DePinho R . FoxO1 is a positive regulator of bone formation by favoring protein synthesis and resistance to oxidative stress in osteoblasts. Cell Metab. 2010; 11(2):147-60. PMC: 2820405. DOI: 10.1016/j.cmet.2010.01.001. View

Durbin S, Jackson J, Ryan M, Gigliotti J, Alway S, Tou J . Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats. J Bone Miner Metab. 2013; 32(1):38-47. DOI: 10.1007/s00774-013-0469-2. View

Kitazawa R, Kimble R, Vannice J, Kung V, Pacifici R . Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest. 1994; 94(6):2397-406. PMC: 330070. DOI: 10.1172/JCI117606. View

10.

Goretti Penido M, Alon U . Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012; 27(11):2039-2048. PMC: 3461213. DOI: 10.1007/s00467-012-2175-z. View

11.

Jilka R, Almeida M, Ambrogini E, Han L, Roberson P, Weinstein R . Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration. Aging Cell. 2010; 9(5):851-67. PMC: 2958819. DOI: 10.1111/j.1474-9726.2010.00616.x. View

12.

Bartell S, Kim H, Ambrogini E, Han L, Iyer S, Serra Ucer S . FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun. 2014; 5:3773. PMC: 4015330. DOI: 10.1038/ncomms4773. View

13.

Sengupta P . The Laboratory Rat: Relating Its Age With Human's. Int J Prev Med. 2013; 4(6):624-30. PMC: 3733029. View

14.

Habold C, Momken I, Ouadi A, Bekaert V, Brasse D . Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension. J Bone Miner Metab. 2010; 29(1):15-22. DOI: 10.1007/s00774-010-0187-y. View

15.

Zhao H, Li X, Li N, Liu T, Liu J, Li Z . Long-term resveratrol treatment prevents ovariectomy-induced osteopenia in rats without hyperplastic effects on the uterus. Br J Nutr. 2013; 111(5):836-46. DOI: 10.1017/S0007114513003115. View

16.

Jilka R, Noble B, Weinstein R . Osteocyte apoptosis. Bone. 2012; 54(2):264-71. PMC: 3624050. DOI: 10.1016/j.bone.2012.11.038. View

17.

Kostenuik P, Capparelli C, Morony S, Adamu S, Shimamoto G, Shen V . OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology. 2001; 142(10):4295-304. DOI: 10.1210/endo.142.10.8437. View

18.

Manolagas S . From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010; 31(3):266-300. PMC: 3365845. DOI: 10.1210/er.2009-0024. View

19.

Kireev R, Tresguerres A, Garcia C, Ariznavarreta C, Vara E, Tresguerres J . Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro-inflammatory damage. J Pineal Res. 2008; 45(4):394-402. DOI: 10.1111/j.1600-079X.2008.00606.x. View

20.

Gennari L, Bilezikian J . New and developing pharmacotherapy for osteoporosis in men. Expert Opin Pharmacother. 2018; 19(3):253-264. DOI: 10.1080/14656566.2018.1428559. View