Skip to main content
Log in

Noninvasive up-regulation of angiopoietin-2 and fibroblast growth factor-2 in bone marrow by pulsed electromagnetic field therapy

  • Original Article
  • Published:
Journal of Orthopaedic Science

Abstract

Background

Pulsed electromagnetic field (PEMF) therapy has been widely used in clinical practice for bone fracture healing. However, the mechanism of its action remains to be elucidated. Our object was to investigate the mechanism by which PEMF accelerates bone fracture healing.

Methods

We used 20 mice in this study. Ten mice received PEMF for 10 h/day for 1 week via the coils of a PEMF stimulation device (PEMF group), while the remaining 10 mice did not (control group). The femurs were harvested immediately after euthanasia to examine the proteins included in the bone marrow. The proteins examined by Western blotting were growth factors with angiogenetic activities, including tunica interna endothelial cell kinase-2, angiopoietin-1, angiopoietin-2, fibroblast growth factor-2, and vascular endothelial growth factor. The expression levels of angiogenesis-related proteins extracted from the bone marrow of each mouse were compared.

Results

The expression levels of angiopoietin-2 and fibroblast growth factor-2 were significantly higher in the PEMF group than in the control group. This difference suggests that PEMF may induce an angiogenesis-prone environment in the bone marrow. Such angiogenesis acceleration represents one possible mechanism for the acceleration of bone fracture healing by PEMF. There were no significant differences between the two groups for the expression levels of tunica interna endothelial cell kinase-2, angiopoietin-1, and vascular endothelial growth factor. The lack of increase in tunica interna endothelial cell kinase-2 expression may indicate that PEMF does not unnecessarily increase blood vessels in normal bone marrow. The lack of an increase in the expression level of vascular endothelial growth factor suggests that PEMF does not have invasive effects including the induction of hypoxic conditions and inflammation on the bone marrow.

Conclusion

The angiogenesis-promoting function of PEMF may contribute to its mechanism to noninvasively accelerate bone fracture healing.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Bassett CA, Pawluk RJ, Pilla AA. Augmentation of bone repair by inductively coupled electromagnetic fields. Science 1974;184:575–577.

    Article  CAS  PubMed  Google Scholar 

  2. Akai M, Kawashima N, Kimura T, Hayashi K. Electrical stimulation as an adjunct to spinal fusion: a meta-analysis of controlled clinical trials. Bioelectromagnetics 2002;23:496–504.

    Article  PubMed  Google Scholar 

  3. Rubin CT, Donahue HJ, Rubin JE, McLeod KJ. Optimization of electric field parameters for the control of bone remodeling: exploitation of an indigenous mechanism for the prevention of osteopenia. J Bone Miner Res 1993;8(suppl. 2):S573–S581.

    PubMed  Google Scholar 

  4. Bodamyali T, Kanczler JM, Simon B, Blake DR, Stevens CR. Effect of faradic products on direct current-stimulated calvarial organ culture calcium levels. Biochem Biophys Res Commun 1999;264:657–661.

    Article  CAS  PubMed  Google Scholar 

  5. Scott G, King JB. A prospective, double-blind trial of electrical capacitive coupling in the treatment of non-union of long bones. J Bone Joint Surg Am 1994;76:820–826.

    CAS  PubMed  Google Scholar 

  6. Luna Gonzalez F, Lopez Arevalo R, Meschian Coretti S, Urbano Labajos V, Delgado Rufino B. Pulsed electromagnetic stimulation of regenerate bone in lengthening procedures. Acta Orthop Belg 2005;71:571–576.

    PubMed  Google Scholar 

  7. Chang K, Chang WH. Pulsed electromagnetic fields prevent osteoporosis in an ovariectomized female rat model: a prostaglandin E2-associated process. Bioelectromagnetics 2003;24:189–198.

    Article  CAS  PubMed  Google Scholar 

  8. Tabrah F, Hoffmeier M, Gilbert F Jr, Batkin S, Bassett CA. Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J Bone Miner Res 1990;5:437–442.

    Article  CAS  PubMed  Google Scholar 

  9. Li JK, Lin JC, Liu HC, Sun JS, Ruaan RC, Shih C, et al. Comparison of ultrasound and electromagnetic field effects on osteoblast growth. Ultrasound Med Biol 2006;32:769–775.

    Article  PubMed  Google Scholar 

  10. Nagai M, Ota M. Pulsating electromagnetic field stimulates mRNA expression of bone morphogenetic protein-2 and -4. J Dent Res 1994;73:1601–1605.

    CAS  PubMed  Google Scholar 

  11. Tepper OM, Callaghan MJ, Chang EI, Galiano RD, Bhatt KA, Baharestani S, et al. Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2. FASEB J 2004;18:1231–1233.

    CAS  PubMed  Google Scholar 

  12. Ishida M, Fujioka M, Takahashi KA, Arai Y, Kubo T. Electromagnetic fields: a novel prophylaxis for steroid-induced osteonecrosis. Clin Orthop 2008;466:1068–1073.

    Article  PubMed  Google Scholar 

  13. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2006;27:552–558.

    Article  CAS  PubMed  Google Scholar 

  14. Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: which are the important molecules? Injury 2007; 38(suppl. 1):S11–S25.

    Article  PubMed  Google Scholar 

  15. Kanczler JM, Oreffo RO. Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 2008;15:100–114.

    CAS  PubMed  Google Scholar 

  16. Inan M, Alat I, Gurses I, Kekilli E, Kutlu R, Eskin A, et al. Induced angiogenesis with intramedullary direct current: experimental research. Am J Physiol Heart Circ Physiol 2005;288:H705–H709.

    Article  CAS  PubMed  Google Scholar 

  17. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997;277:55–60.

    Article  CAS  PubMed  Google Scholar 

  18. Szebenyi G, Fallon JF. Fibroblast growth factors as multifunctional signaling factors. Int Rev Cytol 1999;185:45–106.

    Article  CAS  PubMed  Google Scholar 

  19. Chen WJ, Jingushi S, Aoyama I, Anzai J, Hirata G, Tamura M, et al. Effects of FGF-2 on metaphyseal fracture repair in rabbit tibiae. J Bone Miner Metab 2004;22:3039.

    Article  Google Scholar 

  20. Kawaguchi H, Nakamura K, Tabata Y, Ikada Y, Aoyama I, Anzai J, et al. Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. J Clin Endocrinol Metab 2001;86:875–880.

    Article  CAS  PubMed  Google Scholar 

  21. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676.

    Article  CAS  PubMed  Google Scholar 

  22. Merenmies J, Parada LF, Henkemeyer M. Receptor tyrosine kinase signaling in vascular development. Cell Growth Differ 1997;8:3–10.

    CAS  PubMed  Google Scholar 

  23. Bassett CA. Fundamental and practical aspects of therapeutic uses of pulsed electromagnetic fields (PEMFs). Crit Rev Biomed Eng 1989;17:451–529.

    CAS  PubMed  Google Scholar 

  24. Dickson KF, Katzman S, Paiement G. The importance of the blood supply in the healing of tibial fractures. Contemp Orthop 1995;30:489–493.

    CAS  PubMed  Google Scholar 

  25. Lalani Z, Wong M, Brey EM, Mikos AG, Duke PJ, Miller MJ, et al. Spatial and temporal localization of FGF-2 and VEGF in healing tooth extraction sockets in a rabbit model. J Oral Maxillofac Surg 2005;63:1500–1508.

    Article  PubMed  Google Scholar 

  26. Schmitt JM, Hwang K, Winn SR, Hollinger JO. Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res 1999;17:269–278.

    Article  CAS  PubMed  Google Scholar 

  27. Yang C, Yang S, Du J, Li J, Xu W, Xiong Y. Vascular endothelial growth factor gene transfection to enhance the repair of avascular necrosis of the femoral head of rabbit. Chin Med J (Engl) 2003;116:1544–1548.

    CAS  Google Scholar 

  28. Carmeliet P. VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 2000;6:1102–1103.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

About this article

Cite this article

Goto, T., Fujioka, M., Ishida, M. et al. Noninvasive up-regulation of angiopoietin-2 and fibroblast growth factor-2 in bone marrow by pulsed electromagnetic field therapy. J Orthop Sci 15, 661–665 (2010). https://doi.org/10.1007/s00776-010-1510-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00776-010-1510-0

Keywords

Navigation