Skip to main content
SpringerLink
Log in

Genistein and Silicon Synergistically Protects Against Ovariectomy-Induced Bone Loss Through Upregulating OPG/RANKL Ratio

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

We have reported that genistein (Gen) and silicon (Si) have synergistic effects on ovariectomy-induced bone loss in rat; however, the potential mechanisms behind this effect were not fully clarified yet. This study was performed to evaluate the bone protective mechanisms of concomitant intake of genistein and silicon in ovariectomized rat by OPG/RANKL axis. Three-month-old Sprague-Dawley female rats were subjected to ovariectomy (OVX) or sham surgery; after surgery, the OVX rats were randomly divided into five groups: OVX-Gen, OVX-Si, OVX-Gen-Si, OVX-E, and OVX. Genistein, silicon, and 17β-estradiol supplementation were started after ovariectomy and continued for 10 weeks. The results showed that genistein and silicon treatment increased the bone mineral density (BMD) of ovariectomized rats. In addition, the BMD of the tibia and femur were highest in the OVX-Gen-Si group compared with OVX-Gen and OVX-Si group (p < 0.05). After 10 weeks treatment with genistein and silicon, the bone structure of ovariectomized rats was recovered, there was no difference of bone histomorphometric parameters between OVX-Gen-Si, OVX-E, and SHAM group (p > 0.05), and there was no difference in the concentration of serum ALP, Ca, P, OPG, and RANKL between OVX-Gen-Si, SHAM, and OVX-E groups (p > 0.05). RT-PCR showed that genistein and silicon treatment could effectively increase the OPG mRNA expression and decreased the RANKL mRNA expression compared to that of the OVX group (p < 0.05), the OPG/RANKL mRNA ratios were significantly decreased in the OVX group (p < 0.05), and it was nearly to normal in the OVX-Gen-Si group. Immunohistochemical staining results showed that genistein and silicon supplementation could effectively increase the protein expression of OPG and decrease the protein expression of RANKL in bone tissues; there were no significant differences in OPG and RANKL positive expression areas between OVX-Gen-Si, SHAM, and OVX-E group (p > 0.05). The results above indicate that genistein and silicon supplementation can effectively reduce RANKL, increase OPG levels, and OPG/RANKL ratios in the serum and bone tissue of ovariectomized rats; this is the main mechanism by which genistein and silicon play a bone protective role in ovariectomized rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Bijelic R, Milicevic S, Balaban J (2017) Risk factors for osteoporosis in postmenopausal women. Mediev Archaeol 71:25–28

    Google Scholar 

  2. Rachner TD, Khosla S, Hofbauer LC (2011) Osteoporosis: now and the future. Lancet 377(9773):1276–1287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sun FF, Shi HR (2014) Progress of hormone replacement therapy and breast cancer. Int J Gynecol Obstet 41:146–149

    Google Scholar 

  4. Marsden J (2002) The menopause, hormone replacement therapy and breast cancer. J Steroid Biochem Mol Biol 83(1):123–132

    Article  CAS  PubMed  Google Scholar 

  5. Miraj S (2016) Scientific basis for the therapeutic use of soybean: a review study. Pharm Lett 8(19):421–425

    CAS  Google Scholar 

  6. Levis S, Strickman S, Ganjei P et al (2011) Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. Arch Intern Med 171:1363–1369

    Article  CAS  PubMed  Google Scholar 

  7. Messina M (2014) Soy foods, isoflavones, and the health of postmenopausal women. Am J Clin Nutr 100(1):423S

    Article  CAS  PubMed  Google Scholar 

  8. Zhang X, Shu XO, Li H et al (2005) Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch Intern Med 165:1890–1895

    Article  PubMed  Google Scholar 

  9. Gail AG, Gordon FG, Huang MH et al (2002) Dietary soy isoflavones and bone mineral density: results from the study of women’s health across the nation. Am J Epidemiol 15(8):746–754

    Google Scholar 

  10. Qi SS (2018) Synergistic effects of genistein and zinc on bone metabolism and the femoral metaphyseal histomorphology in the ovariectomized rats. Biol Trace Elem Res 183(2):288–295

    Article  CAS  PubMed  Google Scholar 

  11. Jugdaohsingh R (2007) Silicon and bone health. J Nutr Health Aging 11:99–110

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Bae YJ, Kim JY, Choi MK, Chung YS, Kim MH (2008) Short-term administration of water-soluble silicon improves mineral density of the femur and tibia in ovariectomized rats. Biol Trace Elem Res 124:157–163

    Article  CAS  PubMed  Google Scholar 

  13. Kim MH, Bae YJ, Choi MK, Chung YS (2009) Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption. Biol Trace Elem Res 128:239–247

    Article  CAS  PubMed  Google Scholar 

  14. Jugdaohsingh R, Tucker KL, Qiao N (2010) Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the framingham offspring cohort. J Bone Miner Res 19(2):297–307

    Article  CAS  Google Scholar 

  15. Khosla S, Melton LJ, Riggs BL (2011) The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res 26:441–451

    Article  CAS  PubMed  Google Scholar 

  16. Qi SS, Zheng HX (2017) Combined effects of phytoestrogen genistein and silicon on ovariectomy-induced bone loss in rat. Biol Trace Elem Res 177(2):281–285

    Article  CAS  PubMed  Google Scholar 

  17. Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 15(2):139–146

    Article  CAS  Google Scholar 

  18. Anna E, Silvia RG, Pilar P et al (2010) The effect of the alendronate on OPG/RANKL system in differentiated primary human osteoblasts. Endocrine 37(2):322–328

    Article  CAS  Google Scholar 

  19. Liu JM, Zhao HY, Ning G et al (2005) Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20–75. Calcif Tissue Int 76(1):1–6

    Article  CAS  PubMed  Google Scholar 

  20. Hao Y, Gao R, Lu B et al (2018) Ghrelin protects against depleted uranium-induced bone damage by increasing osteoprotegerin/RANKL ratio. Toxicol Appl Pharmacol 343(15):62–70

    Article  CAS  PubMed  Google Scholar 

  21. Bin J, Li X, Qi Z et al (2014) A hypomagnetic field aggravates bone loss induced by hindlimb unloading in rat Femurs. PLoS One 9(8):e105604

    Article  CAS  Google Scholar 

  22. Seeman E (2004) Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep 2(3):90–96

    Article  PubMed  Google Scholar 

  23. Zhou L, Liu Q, Yang M et al (2016) Dihydroartemisinin, an anti-malaria drug, suppresses estrogen deficiency-induced osteoporosis, osteoclast formation, and RANKL-induced signaling pathways. J Bone Miner Res 31(5):964–970

    Article  CAS  PubMed  Google Scholar 

  24. Persson I, Bergkvist L, Lindgren C et al (1997) Hormone replacement therapy and major risk factors for reproductive cancers, osteoporosis, and cardiovascular diseases: evidence of confounding by exposure characteristics. J Clin Epidemiol 50(5):611–618

    Article  CAS  PubMed  Google Scholar 

  25. Anazi AF, Qureshi VF, Javaid K (2011) Preventive effects of phytoestrogens against postmenopausal osteoporosis as compared to the available therapeutic choices: an overview. J Nat Sci Biol Med 2(2):154–163

    Article  CAS  Google Scholar 

  26. Listed N (2007) Effects of the phytoestrogen genistein on bone health in postmenopausal women. Ann Intern Med 146(12):134–137

    Google Scholar 

  27. Hott M, Pollak C, Modrowski D et al (1993) Short-term effects of organic silicon on trabecular bone in mature ovariectomized rats. Calcif Tissue Int 53:174–179

    Article  CAS  PubMed  Google Scholar 

  28. Hofbauer LC, Khosla S, Dunstan CR et al (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15(1):2–12

    Article  CAS  PubMed  Google Scholar 

  29. Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473(2):139–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Crockett JC, Mellis DJ, Scott DI et al (2011) New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis. Osteoporos Int 22(1):1–20

    Article  CAS  PubMed  Google Scholar 

  31. Wang J, He M, Wang G et al (2017) Organic gallium treatment improves osteoporotic fracture healing through affecting the OPG/RANKL ratio and expression of serum inflammatory cytokines in ovariectomized rats. Biol Trace Elem Res. https://doi.org/10.1007/s12011-017-1123-y

  32. Lacey DL, Boyle WJ, Simonet WS et al (2012) Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11(5):401–419

    Article  CAS  PubMed  Google Scholar 

  33. Gonzalo SD, Christian H, Petra K et al (2015) Bone morphogenetic protein signaling in bone homeostasis. Bone 80:43–59

    Article  CAS  Google Scholar 

  34. Karst M, Gorny G, Galvin RJ et al (2004) Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation. J Cell Physiol 200(1):99–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Komori T (2011) Signaling networks in RUNX2-dependent bone development. J Cell Biochem 112(3):750–758

    Article  CAS  PubMed  Google Scholar 

  36. Gade TP, Motley MW, Beattie BJ et al (2011) Imaging of alkaline phosphatase activity in bone tissue. PLoS ONE 6(7):e22608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Watts NB, Jenkins DK, Visor JM et al (2001) Comparison of bone and total alkaline phosphatase and bone mineral density in postmenopausal osteoporotic women treated with alendronate. Osteoporos Int 12:279–288

    Article  CAS  PubMed  Google Scholar 

  38. Mukaiyama K, Kamimura M, Uchiyama S et al (2015) Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. Aging Clin Exp Res 27:413–418

    Article  PubMed  Google Scholar 

  39. Thompson WR, Rubin CT, Rubin J (2012) Mechanical regulation of signaling pathways in bone. Gene 503(2):179–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Day TF, Yang Y (2008) Wnt and hedgehog signaling pathways in bone development. J Bone Joint Surg Am 90(1):19–24

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by the High-end Foreign Experts Recruitment Programme of State Administration of Foreign Experts Affairs (GDT20176100048), the Key Project of Agricultural Science and Technology of Shaanxi Province (2017NY-082), Shaanxi Science and Technology Coordinating Innovation Engineering Program (2015KTTSSF01–03, 2015HBGC-18), Shaanxi Province Key Research and Development Plan (2017SF-074), Research Project of Shaanxi Provincial Education Department (17JK0135), Postodoctoral Project of Shaanxi University of Technology (SLGBH16-03), and Qinling-Bashan Mountains Bioresources Comprehensive Development, Collaborative Innovation Center Research Funds (QBXT-17-9).

Author information

Authors and Affiliations

  1. Chinese-German Joint Laboratory for Natural Product Research, College of Biological Science and Engineering, Qinling-Bashan Mountains Bioresources Comprehensive Development C.I.C, Shaanxi University of Technology, Chaoyang Road, Hantai District, Hanzhong, 723000, Shaanxi Province, China

    Chen Chen & Hongxing Zheng

  2. Vitamin D research institute, Shaanxi University of Technology, Chaoyang Road, Hantai District, Hanzhong, 723000, Shaanxi Province, China

    Shanshan Qi

Authors
  1. Chen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongxing Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shanshan Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hongxing Zheng or Shanshan Qi.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, C., Zheng, H. & Qi, S. Genistein and Silicon Synergistically Protects Against Ovariectomy-Induced Bone Loss Through Upregulating OPG/RANKL Ratio. Biol Trace Elem Res 188, 441–450 (2019). https://doi.org/10.1007/s12011-018-1433-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-018-1433-8

Keywords

Search

Navigation