Skip to main content

Advertisement

SpringerLink
Log in

Ortho-silicic Acid Plays a Protective Role in Glucocorticoid-Induced Osteoporosis via the Akt/Bad Signal Pathway In Vitro and In Vivo

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

Abstract

Glucocorticoid-induced osteoporosis (GIOP) has been the most common form of secondary osteoporosis. Glucocorticoids (GCs) can induce osteocyte and osteoblast apoptosis. Plenty of research has verified that silicon intake would positively affect bone. However, the effects of silicon on GIOP are not investigated. In this study, we assessed the impact of ortho-silicic acid (OSA) on Dex-induced apoptosis of osteocytes by cell apoptosis assays. The apoptosis-related genes, cleaved-caspase-3, Bcl-2, and Bax, were detected by western blotting. Then, we evaluated the possible role of OSA on osteogenesis and osteoclastogenesis with Dex using Alizarin red staining and tartrate-resistant acid phosphatase (TRAP) staining. We also detected the related genes by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting. We then established the GIOP mouse model to evaluate the potential role of OSA in vivo. We found that OSA showed no cytotoxic on osteocytes below 50 μM and prevented MLO-Y4 from Dex-induced apoptosis. We also found that OSA promoted osteogenesis and inhibited osteoclastogenesis with Dex. OSA had a protective effect on GIOP mice via the Akt signal pathway in vivo. In the end, we verified the Akt/Bad signal pathway in vitro, which showed the same results. Our finding demonstrated that OSA could protect osteocytes from apoptosis induced by GCs both in vitro and in vivo. Also, it promoted osteogenesis and inhibited osteoclastogenesis with the exitance of Dex. In conclusion, OSA has the potential value as a therapeutic agent for GIOP.

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

Similar content being viewed by others

Data Availability

All data in this article will be available upon request.

References

  1. Wright NC, Looker AC, Saag KG et al (2014) The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res Off J Am Soc Bone Miner Res 29:2520–2526. https://doi.org/10.1002/jbmr.2269

    Article  Google Scholar 

  2. Adami G, Saag KG (2019) Glucocorticoid-induced osteoporosis update. Curr Opin Rheumatol 31:388–393. https://doi.org/10.1097/BOR.0000000000000608

    Article  CAS  Google Scholar 

  3. Rodella LF, Bonazza V, Labanca M et al (2014) A review of the effects of dietary silicon intake on bone homeostasis and regeneration. J Nutr Health Aging 18:820–826. https://doi.org/10.1007/s12603-014-0555-8

    Article  CAS  Google Scholar 

  4. Choi M-K, Kim M-H (2017) Dietary silicon intake of Korean young adult males and its relation to their bone status. Biol Trace Elem Res 176:89–104. https://doi.org/10.1007/s12011-016-0817-x

    Article  CAS  Google Scholar 

  5. Nielsen FH (2014) Update on the possible nutritional importance of silicon. J Trace Elem Med Biol Organ Soc Miner Trace Elem GMS 28:379–382. https://doi.org/10.1016/j.jtemb.2014.06.024

    Article  CAS  Google Scholar 

  6. Seaborn CD, Nielsen FH (2002) Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver. Biol Trace Elem Res 89:251–261. https://doi.org/10.1385/bter:89:3:251

    Article  CAS  Google Scholar 

  7. Maehira F, Miyagi I, Eguchi Y (2009) Effects of calcium sources and soluble silicate on bone metabolism and the related gene expression in mice. Nutrition 25:581–589. https://doi.org/10.1016/j.nut.2008.10.023

    Article  CAS  Google Scholar 

  8. Reffitt DM, Ogston N, Jugdaohsingh R et al (2003) Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. Bone 32:127–135. https://doi.org/10.1016/s8756-3282(02)00950-x

    Article  CAS  Google Scholar 

  9. Chi H, Kong M, Jiao G et al (2019) The role of orthosilicic acid-induced autophagy on promoting differentiation and mineralization of osteoblastic cells. J Biomater Appl 34:94–103. https://doi.org/10.1177/0885328219837700

    Article  CAS  Google Scholar 

  10. Dong M, Jiao G, Liu H et al (2016) Biological silicon stimulates collagen type 1 and osteocalcin synthesis in human osteoblast-like cells through the BMP-2/Smad/RUNX2 signaling pathway. Biol Trace Elem Res 173:306–315. https://doi.org/10.1007/s12011-016-0686-3

    Article  CAS  Google Scholar 

  11. Zhou H, Jiao G, Dong M et al (2019) Orthosilicic acid accelerates bone formation in human osteoblast-like cells through the PI3K–Akt–mTOR pathway. Biol Trace Elem Res 190:327–335. https://doi.org/10.1007/s12011-018-1574-9

    Article  CAS  Google Scholar 

  12. Zhou X, Moussa FM, Mankoci S et al (2016) Orthosilicic acid, Si(OH)4, stimulates osteoblast differentiation in vitro by upregulating miR-146a to antagonize NF-κB activation. Acta Biomater 39:192–202. https://doi.org/10.1016/j.actbio.2016.05.007

    Article  CAS  Google Scholar 

  13. You Y, Ma W, Wang F et al (2021) Ortho-silicic acid enhances osteogenesis of osteoblasts through the upregulation of miR-130b which directly targets PTEN. Life Sci 264:118680. https://doi.org/10.1016/j.lfs.2020.118680

    Article  CAS  Google Scholar 

  14. Ma W, Wang F, You Y et al (2021) Ortho-silicic acid inhibits RANKL-induced osteoclastogenesis and reverses ovariectomy-induced bone loss in vivo. Biol Trace Elem Res 199:1864–1876. https://doi.org/10.1007/s12011-020-02286-6

    Article  CAS  Google Scholar 

  15. Schorey JS, Cooper AM (2003) Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell Microbiol 5:133–142. https://doi.org/10.1046/j.1462-5822.2003.00263.x

    Article  CAS  Google Scholar 

  16. Datta SR, Dudek H, Tao X et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241. https://doi.org/10.1016/s0092-8674(00)80405-5

    Article  CAS  Google Scholar 

  17. Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321. https://doi.org/10.1126/science.282.5392.1318

    Article  CAS  Google Scholar 

  18. Revathidevi S, Munirajan AK (2019) Akt in cancer: Mediator and more. Semin Cancer Biol 59:80–91. https://doi.org/10.1016/j.semcancer.2019.06.002

    Article  CAS  Google Scholar 

  19. Tao S-C, Yuan T, Rui B-Y et al (2017) Exosomes derived from human platelet-rich plasma prevent apoptosis induced by glucocorticoid-associated endoplasmic reticulum stress in rat osteonecrosis of the femoral head via the Akt/Bad/Bcl-2 signal pathway. Theranostics 7:733–750. https://doi.org/10.7150/thno.17450

    Article  CAS  Google Scholar 

  20. Kuang M, Zhang W, He W et al (2019) Naringin regulates bone metabolism in glucocorticoid-induced osteonecrosis of the femoral head via the Akt/Bad signal cascades. Chem Biol Interact 304:97–105. https://doi.org/10.1016/j.cbi.2019.03.008

    Article  CAS  Google Scholar 

  21. Kuang M, Huang Y, Zhao X et al (2019) Exosomes derived from Wharton’s jelly of human umbilical cord mesenchymal stem cells reduce osteocyte apoptosis in glucocorticoid-induced osteonecrosis of the femoral head in rats via the miR-21-PTEN-AKT signalling pathway. Int J Biol Sci 15:1861–1871. https://doi.org/10.7150/ijbs.32262

    Article  CAS  Google Scholar 

  22. Xu D, Gao Y, Hu N et al (2017) miR-365 ameliorates dexamethasone-induced suppression of osteogenesis in MC3T3-E1 cells by targeting HDAC4. Int J Mol Sci 18:E977. https://doi.org/10.3390/ijms18050977

    Article  CAS  Google Scholar 

  23. Song L, Cao L, Liu R et al (2020) The critical role of T cells in glucocorticoid-induced osteoporosis. Cell Death Dis 12:45. https://doi.org/10.1038/s41419-020-03249-4

    Article  CAS  Google Scholar 

  24. Jugdaohsingh R, Hui M, Anderson SH et al (2013) The silicon supplement “Monomethylsilanetriol” is safe and increases the body pool of silicon in healthy Pre-menopausal women. Nutr Metab 10:37. https://doi.org/10.1186/1743-7075-10-37

    Article  CAS  Google Scholar 

  25. Storlino G, Colaianni G, Sanesi L et al (2020) Irisin prevents disuse-induced osteocyte apoptosis. J Bone Miner Res 35:766–775. https://doi.org/10.1002/jbmr.3944

    Article  CAS  Google Scholar 

  26. Ensrud KE, Crandall CJ (2017) Osteoporosis. Ann Intern Med 167:ITC17–ITC32. https://doi.org/10.7326/AITC201708010

  27. Chotiyarnwong P, McCloskey EV (2020) Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol 16:437–447. https://doi.org/10.1038/s41574-020-0341-0

    Article  Google Scholar 

  28. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res Off J Am Soc Bone Miner Res 26:229–238. https://doi.org/10.1002/jbmr.320

    Article  CAS  Google Scholar 

  29. Robling AG, Bonewald LF (2020) The osteocyte: new insights. Annu Rev Physiol 82:485–506. https://doi.org/10.1146/annurev-physiol-021119-034332

    Article  CAS  Google Scholar 

  30. Bakker AD, Klein-Nulend J, Tanck E et al (2005) Additive effects of estrogen and mechanical stress on nitric oxide and prostaglandin E2 production by bone cells from osteoporotic donors. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 16:983–989. https://doi.org/10.1007/s00198-004-1785-0

    Article  CAS  Google Scholar 

  31. Lu XL, Huo B, Chiang V, Guo XE (2012) Osteocytic network is more responsive in calcium signaling than osteoblastic network under fluid flow. J Bone Miner Res Off J Am Soc Bone Miner Res 27:563–574. https://doi.org/10.1002/jbmr.1474

    Article  CAS  Google Scholar 

  32. Feng JQ, Ward LM, Liu S et al (2006) Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet 38:1310–1315. https://doi.org/10.1038/ng1905

    Article  CAS  Google Scholar 

  33. Karsenty G (2017) Update on the biology of osteocalcin. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 23:1270–1274. https://doi.org/10.4158/EP171966.RA

    Article  Google Scholar 

  34. Sripanyakorn S, Jugdaohsingh R, Dissayabutr W et al (2009) The comparative absorption of silicon from different foods and food supplements. Br J Nutr 102:825–834. https://doi.org/10.1017/S0007114509311757

    Article  CAS  Google Scholar 

  35. Verborgt O, Gibson GJ, Schaffler MB (2000) Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res Off J Am Soc Bone Miner Res 15:60–67. https://doi.org/10.1359/jbmr.2000.15.1.60

    Article  CAS  Google Scholar 

  36. Tang Y-H, Yue Z-S, Xin D-W et al (2018) β-Ecdysterone promotes autophagy and inhibits apoptosis in osteoporotic rats. Mol Med Rep 17:1591–1598. https://doi.org/10.3892/mmr.2017.8053

    Article  CAS  Google Scholar 

  37. Vahabzadeh S, Roy M, Bose S (2015) Effects of silicon on osteoclast cell mediated degradation, in vivo osteogenesis and vasculogenesis of brushite cement. J Mater Chem B 3:8973–8982. https://doi.org/10.1039/C5TB01081K

    Article  CAS  Google Scholar 

  38. Mladenović Ž, Johansson A, Willman B et al (2014) Soluble silica inhibits osteoclast formation and bone resorption in vitro. Acta Biomater 10:406–418. https://doi.org/10.1016/j.actbio.2013.08.039

    Article  CAS  Google Scholar 

  39. Hott M, de Pollak C, Modrowski D, Marie PJ (1993) Short-term effects of organic silicon on trabecular bone in mature ovariectomized rats. Calcif Tissue Int 53:174–179. https://doi.org/10.1007/BF01321834

    Article  CAS  Google Scholar 

  40. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282. https://doi.org/10.1172/JCI2799

    Article  CAS  Google Scholar 

  41. Chae YC, Vaira V, Caino MC et al (2016) Mitochondrial Akt regulation of hypoxic tumor reprogramming. Cancer Cell 30:257–272. https://doi.org/10.1016/j.ccell.2016.07.004

    Article  CAS  Google Scholar 

  42. Su C-C, Yang J-Y, Leu H-B et al (2012) Mitochondrial Akt-regulated mitochondrial apoptosis signaling in cardiac muscle cells. Am J Physiol Heart Circ Physiol 302:H716-723. https://doi.org/10.1152/ajpheart.00455.2011

    Article  CAS  Google Scholar 

  43. del Peso L, González-García M, Page C et al (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689. https://doi.org/10.1126/science.278.5338.687

    Article  Google Scholar 

  44. Yang J, Liu X, Bhalla K et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132. https://doi.org/10.1126/science.275.5303.1129

    Article  CAS  Google Scholar 

  45. Kokkinopoulou I, Moutsatsou P (2021) Mitochondrial glucocorticoid receptors and their actions. Int J Mol Sci 22:6054. https://doi.org/10.3390/ijms22116054

    Article  CAS  Google Scholar 

  46. Passaquin AC, Lhote P, Rüegg UT (1998) Calcium influx inhibition by steroids and analogs in C2C12 skeletal muscle cells. Br J Pharmacol 124:1751–1759. https://doi.org/10.1038/sj.bjp.0702036

    Article  CAS  Google Scholar 

  47. Bravo-Sagua R, Parra V, López-Crisosto C et al (2017) Calcium transport and signaling in mitochondria. Compr Physiol 7:623–634. https://doi.org/10.1002/cphy.c160013

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

Funding

We received financial support from the Clinical Medicine Science and Technology Innovation Plan of Jinan Science and Technology Bureau (Grant No. 201805042) and Natural Science Foundation of Shandong Province Youth Project (Grant No. ZR2020QH080).

Author information

Authors and Affiliations

  1. Qilu Hospital of Shandong University, Jinan, Shandong, China

    Guanghui Gu & Dehui Hou

  2. Department of Spine Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Guanghui Gu, Dehui Hou, Guangjun Jiao, Wenliang Wu, Hongliang Wang & Yunzhen Chen

  3. Department of Spine Surgery, Linyi Central Hospital, Linyi, Shandong, China

    Hongming Zhou

Authors
  1. Guanghui Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dehui Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guangjun Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenliang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongming Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongliang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yunzhen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Guanghui Gu; data curation: Dehui Hou; formal analysis: Wenliang Wu; funding acquisition: Yunzhen Chen; investigation: Guanghui Gu; methodology: Guanghui Gu; project administration: Yunzhen Chen; resources: Hongliang Wang; software: Hongming Zhou; supervision: Yunzhen Chen; validation: Hongliang Wang; writing-original; draft: Guanghui Gu; writing-review and editing: Guangjun Jiao.

Corresponding author

Correspondence to Yunzhen Chen.

Ethics declarations

Ethics Approval

All animal experiments were performed in accordance with the principles and procedures of the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and the guidelines for the animal treatment of Qilu Hospital of Shandong University (Jinan, China).

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gu, G., Hou, D., Jiao, G. et al. Ortho-silicic Acid Plays a Protective Role in Glucocorticoid-Induced Osteoporosis via the Akt/Bad Signal Pathway In Vitro and In Vivo. Biol Trace Elem Res 201, 843–855 (2023). https://doi.org/10.1007/s12011-022-03201-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-022-03201-x

Keywords

Search

Navigation