Rheumatology International

, Volume 33, Issue 5, pp 1135–1141 | Cite as

Pulsed electromagnetic field stimulates osteoprotegerin and reduces RANKL expression in ovariectomized rats

  • Jun Zhou
  • Shiju Chen
  • Hua Guo
  • Lu Xia
  • Huifang Liu
  • Yuxi Qin
  • Chengqi HeEmail author
Original Article


Pulsed electromagnetic field (PEMF) has been shown to increase bone mineral density in osteoporosis patients and prevent bone loss in ovariectomized rats. But the mechanisms through which PEMF elicits these favorable biological responses are still not fully understood. Receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) are cytokines predominantly secreted by osteoblasts and play a central role in differentiation and functional activation of osteoclasts. The purpose of this study was to investigate the effects of PEMF on RANKL and OPG expression in ovariectomized rats. Thirty 3-month-old female Sprague–Dawley rats were randomly divided into three groups: sham-operated control (Sham), ovariectomy control (OVX), and ovariectomy with PEMF treatment (PEMF). After 12-week interventions, the results showed that PEMF increased serum 17β-estradiol level, reduced serum tartrate-resistant acid phosphatase level, increased bone mineral density, and inhibited deterioration of bone microarchitecture and strength in OVX rats. Furthermore, PEMF could suppress RANKL expression and improve OPG expression in bone marrow cells of OVX rats. In conclusion, this study suggests that PEMF can prevent ovariectomy-induced bone loss through regulating the expression of RANKL and OPG.


Pulsed electromagnetic field Osetoporosis Osteoclast Osteoprotegerin Receptor activator of nuclear factor κB ligand 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Klibanski A, Adams-Campbell L, Bassford T et al (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285(6):785–795. doi: 10.1001/jama.285.6.785 CrossRefGoogle Scholar
  2. 2.
    Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society (2010) Menopause 17(1):25–54; quiz 55–26. doi: 10.1097/gme.0b013e3181c617e6
  3. 3.
    Lewiecki EM (2009) Current and emerging pharmacologic therapies for the management of postmenopausal osteoporosis. J Womens Health (Larchmt) 18(10):1615–1626. doi: 10.1089/jwh.2008.1086 CrossRefGoogle Scholar
  4. 4.
    Gallacher SJ, Dixon T (2010) Impact of treatments for postmenopausal osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate, and denosumab) on bone quality: a systematic review. Calcif Tissue Int 87(6):469–484. doi: 10.1007/s00223-010-9420-x PubMedCrossRefGoogle Scholar
  5. 5.
    Garland DE, Adkins RH, Matsuno NN et al (1999) The effect of pulsed electromagnetic fields on osteoporosis at the knee in individuals with spinal cord injury. J Spinal Cord Med 22(4):239–245PubMedGoogle Scholar
  6. 6.
    Tabrah F, Hoffmeier M, Gilbert F et al (1990) Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J Bone Miner Res 5(5):437–442. doi: 10.1002/jbmr.5650050504 PubMedCrossRefGoogle Scholar
  7. 7.
    Sert C, Mustafa D, Duz MZ et al (2002) The preventive effect on bone loss of 50-Hz, 1-mT electromagnetic field in ovariectomized rats. J Bone Miner Metab 20(6):345–349. doi: 10.1007/s007740200050 PubMedCrossRefGoogle Scholar
  8. 8.
    Chang K, Chang WH (2003) Pulsed electromagnetic fields prevent osteoporosis in an ovariectomized female rat model: a prostaglandin E2-associated process. Bioelectromagnetics 24(3):189–198. doi: 10.1002/bem.10078 PubMedCrossRefGoogle Scholar
  9. 9.
    Jing D, Shen G, Huang J et al (2010) Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. Bone 46(2):487–495. doi: 10.1016/j.bone.2009.09.021 PubMedCrossRefGoogle Scholar
  10. 10.
    Henriksen K, Neutzsky-Wulff AV, Bonewald LF et al (2009) Local communication on and within bone controls bone remodeling. Bone 44(6):1026–1033. doi: 10.1016/j.bone.2009.03.671 PubMedCrossRefGoogle Scholar
  11. 11.
    Martin T, Gooi JH, Sims NA (2009) Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr 19(1):73–88PubMedCrossRefGoogle Scholar
  12. 12.
    Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473(2):139–146. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  13. 13.
    Simonet WS, Lacey DL, Dunstan CR et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89(2):309–319PubMedCrossRefGoogle Scholar
  14. 14.
    Chang K, Chang WH, Huang S et al (2005) Pulsed electromagnetic fields stimulation affects osteoclast formation by modulation of osteoprotegerin, RANK ligand and macrophage colony-stimulating factor. J Orthop Res 23(6):1308–1314. doi: 10.1016/j.orthres.2005.03.012.1100230611 PubMedGoogle Scholar
  15. 15.
    Chen J, Huang LQ, Xia QJ et al (2011) Effects of pulsed electromagnetic fields on the mRNA expression of CAII and RANK in ovariectomized rats. Rheumatol Int. doi: 10.1007/s00296-010-1740-7 Google Scholar
  16. 16.
    Gregory LS, Kelly WL, Reid RC et al (2006) Inhibitors of cyclo-oxygenase-2 and secretory phospholipase A2 preserve bone architecture following ovariectomy in adult rats. Bone 39(1):134–142. doi: 10.1016/j.bone.2005.12.017 PubMedCrossRefGoogle Scholar
  17. 17.
    Li S, Luo Q, Huang L et al (2011) Effects of pulsed electromagnetic fields on cartilage apoptosis signalling pathways in ovariectomised rats. Int Orthop 35(12):1875–1882. doi: 10.1007/s00264-011-1245-3 PubMedCrossRefGoogle Scholar
  18. 18.
    Sakagami N, Amizuka N, Li M et al (2005) Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice. Micron 36(7–8):688–695. doi: 10.1016/j.micron.2005.06.008 PubMedCrossRefGoogle Scholar
  19. 19.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408. doi: 10.1006/meth.2001.1262 PubMedCrossRefGoogle Scholar
  20. 20.
    Luo Q, Li SS, He C et al (2009) Pulse electromagnetic fields effects on serum E2 levels, chondrocyte apoptosis, and matrix metalloproteinase-13 expression in ovariectomized rats. Rheumatol Int 29(8):927–935. doi: 10.1007/s00296-008-0782-6 PubMedCrossRefGoogle Scholar
  21. 21.
    Ominsky MS, Li X, Asuncion FJ et al (2008) RANKL inhibition with osteoprotegerin increases bone strength by improving cortical and trabecular bone architecture in ovariectomized rats. J Bone Miner Res 23(5):672–682. doi: 10.1359/jbmr.080109 PubMedCrossRefGoogle Scholar
  22. 22.
    Kanis JA, Melton LJ 3rd, Christiansen C et al (1994) The diagnosis of osteoporosis. J Bone Miner Res 9(8):1137–1141. doi: 10.1002/jbmr.5650090802 PubMedCrossRefGoogle Scholar
  23. 23.
    Bonnick SL, Shulman L (2006) Monitoring osteoporosis therapy: bone mineral density, bone turnover markers, or both? Am J Med 119(4 Suppl 1):S25–S31. doi: 10.1016/j.amjmed.2005.12.020 PubMedCrossRefGoogle Scholar
  24. 24.
    Wronski TJ, Dann LM, Scott KS et al (1989) Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 45(6):360–366PubMedCrossRefGoogle Scholar
  25. 25.
    Friedman AW (2006) Important determinants of bone strength: beyond bone mineral density. J Clin Rheumatol 12(2):70–77. doi: 10.1097/01.rhu.0000208612.33819.8c PubMedCrossRefGoogle Scholar
  26. 26.
    Ulrich D, Van Rietbergen B, Laib A et al (1999) The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone. Bone 25(1):55–60PubMedCrossRefGoogle Scholar
  27. 27.
    Van der Linden JC, Homminga J, Verhaar JA et al (2001) Mechanical consequences of bone loss in cancellous bone. J Bone Miner Res 16(3):457–465. doi: 10.1359/jbmr.2001.16.3.457 PubMedCrossRefGoogle Scholar
  28. 28.
    Suda T, Takahashi N, Martin TJ (1992) Modulation of osteoclast differentiation. Endocr Rev 13(1):66–80PubMedGoogle Scholar
  29. 29.
    Dougall WC, Glaccum M, Charrier K et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13(18):2412–2424PubMedCrossRefGoogle Scholar
  30. 30.
    Lacey DL, Timms E, Tan HL et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93(2):165–176PubMedCrossRefGoogle Scholar
  31. 31.
    Burgess TL, Qian Y, Kaufman S et al (1999) The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J Cell Biol 145(3):527–538PubMedCrossRefGoogle Scholar
  32. 32.
    Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29(2):155–192. doi: 10.1210/er.2007-0014 PubMedCrossRefGoogle Scholar
  33. 33.
    Chang K, Hong-Shong Chang W, Yu YH et al (2004) Pulsed electromagnetic field stimulation of bone marrow cells derived from ovariectomized rats affects osteoclast formation and local factor production. Bioelectromagnetics 25(2):134–141. doi: 10.1002/bem.10168 PubMedCrossRefGoogle Scholar
  34. 34.
    Chang K, Chang WH, Tsai MT et al (2006) Pulsed electromagnetic fields accelerate apoptotic rate in osteoclasts. Connect Tissue Res 47(4):222–228. doi: 10.1080/03008200600858783 PubMedCrossRefGoogle Scholar
  35. 35.
    Chang WH, Chen LT, Sun JS et al (2004) Effect of pulse-burst electromagnetic field stimulation on osteoblast cell activities. Bioelectromagnetics 25(6):457–465. doi: 10.1002/bem.20016 PubMedCrossRefGoogle Scholar
  36. 36.
    Miyazaki T, Matsunaga T, Miyazaki S et al (2004) Changes in receptor activator of nuclear factor-kappaB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats. J Cell Biochem 93(3):503–512. doi: 10.1002/jcb.20201 PubMedCrossRefGoogle Scholar
  37. 37.
    Wang FS, Ko JY, Lin CL et al (2007) Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats. Bone 40(2):485–492. doi: 10.1016/j.bone.2006.09.004 Google Scholar
  38. 38.
    Nagai M, Sato N (1999) Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation. Biochem Biophys Res Commun 257(3):719–723. doi: 10.1006/bbrc.1999.0524 PubMedCrossRefGoogle Scholar
  39. 39.
    Nakagawa N, Yasuda H, Yano K et al (1999) Basic fibroblast growth factor induces osteoclast formation by reciprocally regulating the production of osteoclast differentiation factor and osteoclastogenesis inhibitory factor in mouse osteoblastic cells. Biochem Biophys Res Commun 265(1):158–163. doi: 10.1006/bbrc.1999.1601 PubMedCrossRefGoogle Scholar
  40. 40.
    Bord S, Ireland DC, Beavan SR et al (2003) The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32(2):136–141PubMedCrossRefGoogle Scholar
  41. 41.
    Bord S, Frith E, Ireland DC et al (2004) Synthesis of osteoprotegerin and RANKL by megakaryocytes is modulated by oestrogen. Br J Haematol 126(2):244–251. doi: 10.1111/j.1365-2141.2004.05024.x PubMedCrossRefGoogle Scholar
  42. 42.
    Hofbauer LC, Khosla S, Dunstan CR et al (1999) Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140(9):4367–4370PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Jun Zhou
    • 1
    • 2
    • 3
  • Shiju Chen
    • 1
    • 2
  • Hua Guo
    • 1
    • 2
  • Lu Xia
    • 1
    • 2
  • Huifang Liu
    • 1
    • 2
  • Yuxi Qin
    • 1
    • 2
  • Chengqi He
    • 1
    • 2
    Email author
  1. 1.Department of Rehabilitation, West China HospitalSichuan UniversityChengduPeople’s Republic of China
  2. 2.Rehabilitation Key Laboratory of Sichuan ProvinceChengduPeople’s Republic of China
  3. 3.Department of RehabilitationThe First Affiliated Hospital of University of South ChinaHengyanPeople’s Republic of China

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