Skip to main content

Advertisement

SpringerLink
Log in

Fructose 1,6-bisphosphate inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB/NFATc-1

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Background

Although some glycolytic intermediates have been shown to modulate several cell type formation and activation, the functional role of fructose 1,6-bisphosphate (FBP) on osteoclastogenesis is still unknown.

Methods

Osteoclastogenesis was evaluated on bone marrow preosteoclasts cultured with M-CSF − 30 ng/ml, RANKL − 10 ng/ml, and two concentrations of FBP (100 and 300 µM). TRAP-positive stained cells were counted, and osteoclastogenic marker genes expression were evaluated by qPCR. Osteoclasts resorption capacity was evaluated by the expression of specific enzymes and capacity to resorb a mineralized matrix. The NF-κB activation was detected using RAW 264.7, stably expressing luciferase on the NF-κB responsive promoter.

Results

We show that FBP, the product of the first stage of glycolysis, inhibited RANKL-induced osteoclasts differentiation and TRAP activity. The treatment of preosteoclasts with FBP attenuated osteoclast fusion and formation, without affecting cell viability. Moreover, the inhibition of several osteoclastogenic marker genes expression (TRAP, OSCAR, DC-STAMP, Integrin αv, NFATc1) by FBP correlates with a reduction of mineralized matrix resorption capacity. The mechanism underlying FBP-inhibition of osteoclastogenesis involves NF-κB/NFATc1 signaling pathway inhibition.

Conclusion

Altogether these data show a protective role of a natural glycolytic intermediate in bone homeostasis that may have therapeutic benefit for osteolytic diseases.

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

References

  1. Alford AI, Kozloff KM, Hankenson KD. Extracellular matrix networks in bone remodeling. Int J Biochem Cell Biol. 2015;65:20–31.

    Article  PubMed  CAS  Google Scholar 

  2. Adamopoulos IE, Mellins ED. Alternative pathways of osteoclastogenesis in inflammatory arthritis. Nat Rev Rheumatol. 2015;11:189–94.

    Article  PubMed  CAS  Google Scholar 

  3. Leidig-Bruckner G, Ziegler R. Diabetes mellitus a risk for osteoporosis? Exp Clin Endocrinol Diabetes. 2001;109(Suppl 2):493–514.

    Article  Google Scholar 

  4. Kim JH, Kim N. Regulation of NFATc1 in osteoclast differentiation. Journal of Bone Metabolism. 2014;21:233–41.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Takayanagi H, Kim S, Koga T, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3:889–901.

    Article  PubMed  CAS  Google Scholar 

  6. Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. 2007;40:251–64.

    Article  PubMed  CAS  Google Scholar 

  7. Kim JM, Jeong D, Kang HK, Jung SY, et al. Osteoclast precursors display dynamic metabolic shifts toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation. Cell Physiol Biochem. 2007;20:935–46.

    Article  PubMed  CAS  Google Scholar 

  8. Lee YS, Kim YS, Lee SY, Kim GH, Kim BJ, Lee SH, et al. AMP-kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts. Bone. 2010;47:926–37.

    Article  PubMed  CAS  Google Scholar 

  9. Fong JE, Le Nihouannen D, Tiedemann K, Sadvakassova G, Barralet JE, Komarova SV. Moderate excess of pyruvate augments osteoclastogenesis. Biol Open. 2013;22(2(4):387–95.

    Article  CAS  Google Scholar 

  10. Williams JP, Blair HC, McDonald JM, et al. Regulation of osteoclastic bone resorption by glucose. Biochem Biophys Res Commun. 1997;235:646–51.

    Article  PubMed  CAS  Google Scholar 

  11. Ahn H, Lee K, Kim JM, Kwon SH, Lee SH, Lee SY, Jeong D. Accelerated lactate dehydrogenase activity potentiates osteoclastogenesis via NFATc1 signaling. PLoS One. 2016;11:e0153886.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Indo Y, Takeshita S, Ishii KA, Hoshii T, Aburatani H, Hirao A, Ikeda K. Metabolic regulation of osteoclast differentiation and function. J Bone Miner Res. 2013;28:2392–9.

    Article  PubMed  CAS  Google Scholar 

  13. Jones W, Bianchi K. Aerobic glycolysis: beyond proliferation. Front Immunol. 2015;15:6:227.

    Google Scholar 

  14. Cohen JE, Atluri P, Taylor MD, Grand TJ, Liao GP, Panlilio CM, et al. Fructose 1,6-diphosphate administration attenuates post-ischemic ventricular dysfunction. Heart Lung Circ. 2006;15:119–23.

    Article  PubMed  CAS  Google Scholar 

  15. Ahn SM, Hwang JS, Lee SH. Fructose 1,6-diphosphate alleviates UV-induced oxidative skin damage in hairless mice. Biol Pharm Bull. 2007;30:692–7.

    Article  PubMed  CAS  Google Scholar 

  16. Xu K, Stringer JL. Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats. Pharmacol Res. 2008;57:234–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Veras FP, Peres RS, Saraiva AL, Pinto LG, Louzada-Junior P, Cunha TM, et al. Fructose 1,6-bisphosphate, a high-energy intermediate of glycolysis, attenuates experimental arthritis by activating anti-inflammatory adenosinergic pathway. Scientific Reports. 2015;5:15171.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Ma B, Zhang Q, Wu D, Wang YL, Hu YY, Cheng YP, Yang ZD, Zheng YY, Ying HJ. Strontium fructose 1,6-diphosphate prevents bone loss in a rat model of postmenopausal osteoporosis via the OPG/RANKL/RANK pathway. Acta Pharmacol Sin. 2012;33:479–89.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Bordignon Nunes F, Meier Graziottin C, Alves Filho JC, Lunardelli A, Caberlon E, Peres A, Rodrigues De Oliveira J. Immunomodulatory effect of fructose-1,6-bisphosphate on T-lymphocytes. Int Immunopharmacol. 2003;3:267–72.

    Article  PubMed  CAS  Google Scholar 

  20. Shinohara M, Takayanagi H. Analysis of NFATc1-centered transcription factor regulatory networks in osteoclast formation. Methods Mol Biol. 2014;1164:171–6.

    Article  PubMed  CAS  Google Scholar 

  21. Sundaram K, Nishimura R, Senn J, Youssef RF, London SD, Reddy SV. RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res. 2007;313:168–78.

    Article  PubMed  CAS  Google Scholar 

  22. Blair HC, Teitelbaum SL, Grosso LE, et al. Extracellular-matrix degradation at acid pH. Avian osteoclast acid collagenase isolation and characterization. Biochem J. 1993;290(Pt 3):873–84.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-kappaB and c-Fos in osteoclasts. J Bone Miner Metab. 2005;23:11–15.

  24. Yu M, Qi X, Moreno JL, Farber DL, Keegan AD. NF-κB signaling participates in both RANKL- and IL-4-induced macrophage fusion: receptor cross-talk leads to alterations in NF-κB pathways. J Immunol. 2011;187:1797–806.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author’s thanks Mayara Santos Gomes for her technical assistance. This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grant No. 2015/09034-0; 2013/08216-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-130230/2016-2 scholarship to LWB).

Author information

Authors and Affiliations

  1. Ribeirao Preto Medical School, Department of Pharmacology, University of Sao Paulo, Ribeirao Preto, Brazil

    L. Wilches-Buitrago, P. R. Viacava, F. Q. Cunha & J. C. Alves-Filho

  2. School of Pharmaceutical Sciences of Ribeirao Preto, Department of Physics and Chemistry, University of Sao Paulo, Ribeirao Preto, Brazil

    L. Wilches-Buitrago & S. Y. Fukada

Authors
  1. L. Wilches-Buitrago
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. R. Viacava
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Q. Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. C. Alves-Filho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Y. Fukada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Y. Fukada.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Additional information

Responsible Editor: Jason J. McDougall.

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

Wilches-Buitrago, L., Viacava, P., Cunha, F.Q. et al. Fructose 1,6-bisphosphate inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB/NFATc-1. Inflamm. Res. 68, 415–421 (2019). https://doi.org/10.1007/s00011-019-01228-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-019-01228-w

Keywords

Search

Navigation