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Pulsed electromagnetic fields inhibit bone loss in streptozotocin-induced diabetic rats

Abstract

Evidences have shown that pulsed electromagnetic fields (PEMFs) can partially prevent bone loss in streptozotocin (STZ)-induced diabetic rats. However, the precise mechanisms accounting for these favorable effects are unclear. This study aimed to investigate the effects of PEMFs on bone mass and receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) and Wnt/β-catenin signaling pathway in STZ rats. Thirty 3-month-old Sprague Dawley rats were randomly divided into the following three groups (n = 10): control group (injection of saline vehicle), DM group (injection of STZ), and PEMFs group (injection of STZ + PEMFs exposure). One week following injection of STZ, rats in the PEMFs group were subject to PEMFs stimulus for 40 min/day, 5 days/week, and lasted for 12 weeks. After 12 week intervention, the results showed that PEMFs increased serum bone-specific alkaline phosphatase level and bone mineral density, and inhibited deterioration of bone microarchitecture and strength in STZ rats. Furthermore, PEMFs up-regulated the mRNA expressions of low-density lipoprotein receptor-related protein 5, β-catenin and runt-related gene 2 (Runx2), and down-regulated dickkopf1 in STZ rats. However, mRNA expressions of RANKL and OPG were not affected by PEMFs. PEMFs can prevent the diabetes-induced bone loss and reverse the deterioration of bone microarchitecture and strength by restoring Runx2 expression through regulation of Wnt/β-catenin signaling, regardless of its no glucose lowering effect.

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References

  1. L. Guariguata, D.R. Whiting, I. Hambleton, J. Beagley, U. Linnenkamp, J.E. Shaw, Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract. 103, 137–149 (2014)

    Article  CAS  PubMed  Google Scholar 

  2. A. Bener, F. Al-Laftah, A.O. Al-Hamaq, M. Daghash, W.K. Abdullatef, A study of diabetes complications in an endogamous population: an emerging public health burden. Diabetes & Metab. Syndr. 8, 108–114 (2014)

    Article  Google Scholar 

  3. L. Forsen, H. Meyer, K. Midthjell, T.-H. Edna, Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag Health Survey. Diabetologia 42, 920–925 (1999)

    Article  CAS  PubMed  Google Scholar 

  4. A. Herskind, K. Christensen, K. Nørgaard-Andersen, J. Andersen, Diabetes mellitus and healing of closed fractures. Diabète & métabolisme 18, 63 (1992)

    CAS  Google Scholar 

  5. H.F. Liu, L. Yang, H.C. He, J. Zhou, Y. Liu, C.Y. Wang, Y.C. Wu, C.Q. He, Pulsed electromagnetic fields on postmenopausal osteoporosis in Southwest China: a randomized, active-controlled clinical trial. Bioelectromagnetics 34, 323–332 (2013)

    Article  CAS  PubMed  Google Scholar 

  6. J. Zhou, S. Chen, H. Guo, L. Xia, H. Liu, Y. Qin, C. He, Pulsed electromagnetic field stimulates osteoprotegerin and reduces RANKL expression in ovariectomized rats. Rheumatol. Int. 33, 1135–1141 (2013)

    Article  CAS  PubMed  Google Scholar 

  7. J. Zhou, H. He, L. Yang, S. Chen, H. Guo, L. Xia, H. Liu, Y. Qin, C. Liu, X. Wei, Y. Zhou, C. He, Effects of pulsed electromagnetic fields on bone mass and Wnt/beta-catenin signaling pathway in ovariectomized rats. Arch. Med. Res. 43, 274–282 (2012)

    Article  CAS  PubMed  Google Scholar 

  8. D. Jing, F. Li, M. Jiang, J. Cai, Y. Wu, K. Xie, X. Wu, C. Tang, J. Liu, W. Guo, G. Shen, E. Luo, Pulsed electromagnetic fields improve bone microstructure and strength in ovariectomized rats through a Wnt/Lrp5/beta-catenin signaling-associated mechanism. PLoS One 8, e79377 (2013)

    Article  PubMed Central  PubMed  Google Scholar 

  9. D Jing, J Cai, Y Wu, G Shen, F Li, Q Xu, K Xie, C Tang, J Liu, W Guo, X Wu, M Jiang, and E Luo, Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats. J. Bone Miner. Res. doi: 10.1002/jbmr.2260. [Epub ahead of print] (2014)

  10. C.H. Lohmann, Z. Schwartz, Y. Liu, H. Guerkov, D.D. Dean, B. Simon, B.D. Boyan, Pulsed electromagnetic field stimulation of MG63 osteoblast-like cells affects differentiation and local factor production. J. Orthop. Res. 18, 637–646 (2000)

    Article  CAS  PubMed  Google Scholar 

  11. M. De Mattei, A. Caruso, G.C. Traina, F. Pezzetti, T. Baroni, V. Sollazzo, Correlation between pulsed electromagnetic fields exposure time and cell proliferation increase in human osteosarcoma cell lines and human normal osteoblast cells in vitro. Bioelectromagnetics 20, 177–182 (1999)

    Article  PubMed  Google Scholar 

  12. K. Chang, W.H. Chang, S. Huang, C. Shih, Pulsed electromagnetic fields stimulation affects osteoclast formation by modulation of osteoprotegerin RANK ligand and macrophage colony-stimulating factor. J. Orthop. Res. 23, 1308–1314 (2005)

    CAS  PubMed  Google Scholar 

  13. C.-C. Guan, M. Yan, X.-Q. Jiang, P. Zhang, X.-L. Zhang, J. Li, D.-X. Ye, F.-Q. Zhang, Sonic hedgehog alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of bone marrow stromal cells. Bone 45, 1146–1152 (2009)

    Article  CAS  PubMed  Google Scholar 

  14. J.H. Kim, Y.-Y. Kim, S.-J. Kim, High glucose inhibits gene expression of tyrosyl-tRNA synthetase in osteoblast cells. Methods Find. Exp. Clin. Pharmacol. 31, 639–644 (2009)

    Article  CAS  PubMed  Google Scholar 

  15. J. Verhaeghe, E. Van Herck, R. Van Bree, K. Moermans, R. Bouillon, Decreased osteoblast activity in spontaneously diabetic rats. Endocrine 7, 165–175 (1997)

    Article  CAS  PubMed  Google Scholar 

  16. Y. Wittrant, Y. Gorin, K. Woodruff, D. Horn, H. Abboud, S. Mohan, S. Abboud-Werner, High d (+) glucose concentration inhibits RANKL-induced osteoclastogenesis. Bone 42, 1122–1130 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Y. Kawashima, J.C. Fritton, S. Yakar, S. Epstein, M.B. Schaffler, K.J. Jepsen, D. LeRoith, Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis. Bone 44, 648–655 (2009)

    Article  PubMed Central  PubMed  Google Scholar 

  18. D. Jing, J. Cai, G. Shen, J. Huang, F. Li, J. Li, L. Lu, E. Luo, Q. Xu, The preventive effects of pulsed electromagnetic fields on diabetic bone loss in streptozotocin-treated rats. Osteoporos. Int. 22, 1885–1895 (2011)

    Article  CAS  PubMed  Google Scholar 

  19. T. Martin, J.H. Gooi, N.A. Sims, Molecular mechanisms in coupling of bone formation to resorption. Crit. Rev. Eukaryot. Gene Expr. 19, 73–88 (2009)

    Article  CAS  PubMed  Google Scholar 

  20. B.F. Boyce, L. Xing, Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys. 473, 139–146 (2008)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. W.S. Simonet, D.L. Lacey, C.R. Dunstan, M. Kelley, M.S. Chang, R. Luthy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, G. Shimamoto, M. DeRose, R. Elliott, A. Colombero, H.L. Tan, G. Trail, J. Sullivan, E. Davy, N. Bucay, L. Renshaw-Gegg, T.M. Hughes, D. Hill, W. Pattison, P. Campbell, S. Sander, G. Van, J. Tarpley, P. Derby, R. Lee, W.J. Boyle, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997)

    Article  CAS  PubMed  Google Scholar 

  22. V. Krishnan, H.U. Bryant, O.A. Macdougald, Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209 (2006)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. P. Diniz, K. Shomura, K. Soejima, G. Ito, Effects of pulsed electromagnetic field (PEMF) stimulation on bone tissue like formation are dependent on the maturation stages of the osteoblasts. Bioelectromagnetics 23, 398–405 (2002)

    Article  PubMed  Google Scholar 

  24. J. Zhou, S. Chen, H. Guo, L. Xia, H. Liu, Y. Qin, C. He, Electroacupuncture prevents ovariectomy-induced osteoporosis in rats: a randomised controlled trial. Acupunct. Med. 30, 37–43 (2012)

    Article  CAS  PubMed  Google Scholar 

  25. M. Hie, M. Yamazaki, I. Tsukamoto, Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes. Eur. J. Pharmacol. 621, 1–9 (2009)

    Article  CAS  PubMed  Google Scholar 

  26. N. Iitsuka, M. Hie, I. Tsukamoto, Zinc supplementation inhibits the increase in osteoclastogenesis and decrease in osteoblastogenesis in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 714, 41–47 (2013)

    Article  CAS  PubMed  Google Scholar 

  27. X. Han, Y. Xu, J. Wang, X. Pei, R. Yang, N. Li, Y. Li, Effects of cod bone gelatin on bone metabolism and bone microarchitecture in ovariectomized rats. Bone 44, 942–947 (2009)

    Article  CAS  PubMed  Google Scholar 

  28. M.S. Ominsky, X. Li, F.J. Asuncion, M. Barrero, K.S. Warmington, D. Dwyer, M. Stolina, Z. Geng, M. Grisanti, H.L. Tan, T. Corbin, J. McCabe, W.S. Simonet, H.Z. Ke, P.J. Kostenuik, RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J. Bone Miner. Res. 23, 672–682 (2008)

    Article  CAS  PubMed  Google Scholar 

  29. W. Liang, Z. Luo, S. Ge, M. Li, J. Du, M. Yang, M. Yan, Z. Ye, Z. Luo, Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia. Eur. J. Pharmacol. 670, 317–324 (2011)

    Article  CAS  PubMed  Google Scholar 

  30. N. Erdal, S. Gürgül, S. Kavak, A. Yildiz, M. Emre, Deterioration of bone quality by streptozotocin (STZ)-induced type 2 diabetes mellitus in rats. Biol. Trace Elem. Res. 140, 342–353 (2011)

    Article  CAS  PubMed  Google Scholar 

  31. E. Tsirella, T. Mavrakanas, O. Rager, S. Tsartsalis, K. Kallaras, B. Kokkas, M. Mironidou-Tzouveleki, Low dose pioglitazone does not affect bone formation and resorption markers or bone mineral density in streptozocin-induced diabetic rats. J. Physiol. Pharmacol. 63, 201–204 (2012)

    CAS  PubMed  Google Scholar 

  32. C.H. Turner, D.B. Burr, Basic biomechanical measurements of bone: a tutorial. Bone 14, 595–608 (1993)

    Article  CAS  PubMed  Google Scholar 

  33. C. Hernandez, T. Keaveny, A biomechanical perspective on bone quality. Bone 39, 1173–1181 (2006)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. W.C. Dougall, M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M.E. Tometsko, C.R. Maliszewski, A. Armstrong, V. Shen, S. Bain, D. Cosman, D. Anderson, P.J. Morrissey, J.J. Peschon, J. Schuh, RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. W.G. Goodman, M.T. Hori, Diminished bone formation in experimental diabetes: relationship to osteoid maturation and mineralization. Diabetes 33, 825–831 (1984)

    Article  CAS  PubMed  Google Scholar 

  36. A. Kikuchi, S. Kishida, H. Yamamoto, Regulation of Wnt signaling by protein–protein interaction and post-translational modifications. Exp. Mol. Med. 38, 1–10 (2006)

    Article  CAS  PubMed  Google Scholar 

  37. T. Gaur, C.J. Lengner, H. Hovhannisyan, R.A. Bhat, P.V. Bodine, B.S. Komm, A. Javed, A.J. van Wijnen, J.L. Stein, G.S. Stein, J.B. Lian, Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132–33140 (2005)

    Article  CAS  PubMed  Google Scholar 

  38. D.G. Monroe, M.E. McGee-Lawrence, M.J. Oursler, J.J. Westendorf, Update on Wnt signaling in bone cell biology and bone disease. Gene 492, 1–18 (2012)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. M. Hie, N. Iitsuka, T. Otsuka, I. Tsukamoto, Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation. Int. J. Mol. Med. 28, 455–462 (2011)

    CAS  PubMed  Google Scholar 

  40. P.V. Bodine, B.S. Komm, Wnt signaling and osteoblastogenesis. Rev. Endocr. Metab. Disord. 7, 33–39 (2006)

    Article  CAS  PubMed  Google Scholar 

  41. C. Hartmann, A Wnt canon orchestrating osteoblastogenesis. Trends Cell Biol. 16, 151–158 (2006)

    Article  CAS  PubMed  Google Scholar 

  42. X. He, M. Semenov, K. Tamai, X. Zeng, LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development 131, 1663–1677 (2004)

    Article  CAS  PubMed  Google Scholar 

  43. J.J. Pinzone, B.M. Hall, N.K. Thudi, M. Vonau, Y.W. Qiang, T.J. Rosol, J.D. Shaughnessy Jr., The role of dickkopf-1 in bone development, homeostasis, and disease. Blood 113, 517–525 (2009)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. F. Otto, A.P. Thornell, T. Crompton, A. Denzel, K.C. Gilmour, I.R. Rosewell, G.W. Stamp, R.S. Beddington, S. Mundlos, B.R. Olsen, P.B. Selby, M.J. Owen, Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997)

    Article  CAS  PubMed  Google Scholar 

  45. M. Hie, I. Tsukamoto, Increased expression of the receptor for activation of NF-κB and decreased runt-related transcription factor 2 expression in bone of rats with streptozotocin-induced diabetes. Int. J. Mol. Med. 26, 611–618 (2010)

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Shiju Chen,MD, and Huifang Liu, MD, for assisting in language editing of this manuscript. We thank Health Department of Hunan Province, China (NO. B2014-052) for the financial support.

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The authors declare that they have no conflict of interest.

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Correspondence to Jun Zhou.

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Zhou, J., Li, X., Liao, Y. et al. Pulsed electromagnetic fields inhibit bone loss in streptozotocin-induced diabetic rats. Endocrine 49, 258–266 (2015). https://doi.org/10.1007/s12020-014-0439-z

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  • DOI: https://doi.org/10.1007/s12020-014-0439-z

Keywords

  • Pulsed electromagnetic fields
  • Diabetes mellitus
  • Streptozotocin
  • RANKL/OPG
  • Wnt/β-catenin signaling