European Spine Journal

, Volume 23, Issue 2, pp 455–462 | Cite as

Selective estrogen receptor modulation prevents scoliotic curve progression: radiologic and histomorphometric study on a bipedal C57Bl6 mice model

  • Gokhan Demirkiran
  • Ozgur Dede
  • Nadir Yalcin
  • Ibrahim Akel
  • Ralph Marcucio
  • Emre Acaroglu
Original Article

Abstract

Purpose

Previous work has suggested that progression of experimental scoliotic curves in pinealectomized chicken and bipedal C57BL6 mice models may be prevented and reversed with Tamoxifen treatment. Raloxifene is another Selective Estrogen Receptor Modulator (SERM) with estrogen agonist effects on bone and increases bone density but with fewer side effects on humans. To investigate whether scoliosis progression in bipedal C57Bl6 mice model could be prevented with SERM treatment and the mechanisms associated with this effect.

Methods

Eighty C57BL6 mice were rendered bipedal and divided into Tamoxifen (TMX), Raloxifene (RLX) and control groups. TMX and RLX groups received orally administered TMX and RLX for 40 weeks. Anteroposterior X-ray imaging and histomorphometric analysis (at 20th and 40th weeks) were performed.

Results

At 20th week, TMX and RLX groups displayed higher rates (p = 0.033, p = 0.029) and larger curve magnitudes (p = 0.018). At 40th week, curve rates were similar between the groups but the curve magnitudes in TMX and RLX groups were smaller (p = 0.001). Histomorphometry revealed that treated animals had higher trabecular density (p = 0.04), lower total intervertebral disc (p = 0.038) and growth plate volumes (p = 0.005) and smaller vertebral bodies (p = 0.016).

Conclusions

Treatment with TMX or RLX did not reduce the incidence of scoliosis but decreased the curve magnitudes at 40 weeks. The underlying mechanism associated with the decrease in curve magnitudes may be the early maturation of growth plates, thereby possible deceleration of the growth rate of the vertebral column and increase in bone density. RLX is as effective as TMX in preventing the progression of scoliotic curves in melatonin deficient bipedal mice.

Keywords

Scoliosis Animal model Bipedal mice Bone density Tamoxifen Raloxifene 

References

  1. 1.
    Ahn UM, Ahn NU, Nallamshetty L et al (2002) The etiology of adolescent idiopathic scoliosis. Am J Orthop (Belle Mead NJ) 31:387–395Google Scholar
  2. 2.
    Inoue M, Minami S, Kitahara H et al (1998) Idiopathic scoliosis in twins studied by DNA fingerprinting: the incidence and type of scoliosis. J Bone Joint Surg Br 80:212–217PubMedCrossRefGoogle Scholar
  3. 3.
    Inoue M, Minami S, Nakata Y et al (2002) Prediction of curve progression in idiopathic scoliosis from gene polymorphic analysis. Stud Health Technol Inform 91:90–96PubMedGoogle Scholar
  4. 4.
    Lowe TG, Edgar M, Margulies JY et al (2000) Etiology of idiopathic scoliosis: current trends in research. J Bone Joint Surg Am 82-A:1157–1168PubMedGoogle Scholar
  5. 5.
    Mei YA, Lee PP, Wei H, Zhang ZH, Pang SF (2001) Melatonin and its analogs potentiate the nifedipine-sensitive high-voltage-activated calcium current in the chick embryonic heart cells. J Pineal Res 30:13–21PubMedCrossRefGoogle Scholar
  6. 6.
    Miller NH (1999) Cause and natural history of adolescent idiopathic scoliosis. Orthop Clin North Am 30:343–52, viiGoogle Scholar
  7. 7.
    Miller NH (2002) Genetics of familial idiopathic scoliosis. Clin Orthop Relat Res 462:60–64CrossRefGoogle Scholar
  8. 8.
    Wang WJ, Yeung HY, Chu WC et al (2011) Top theories for the etiopathogenesis of adolescent idiopathic scoliosis. J Pediatr Orthop 31:S14–S27PubMedCrossRefGoogle Scholar
  9. 9.
    Dubousset J, Queneau P, Thillard MJ (1983) Experimental scoliosis induced by pineal and diencephalic lesions in young chickens. Its relation with clinical findings in idiopathic scoliosis. Orthop Trans 7:7–12Google Scholar
  10. 10.
    Machida M, Dubousset J, Imamura Y, Iwaya T, Yamada T, Kimura J (1995) Role of melatonin deficiency in the development of scoliosis in pinealectomised chickens. J Bone Joint Surg Br 77:134–138PubMedGoogle Scholar
  11. 11.
    Machida M, Dubousset J, Imamura Y et al (1994) Pathogenesis of idiopathic scoliosis: SEPS in chicken with experimentally induced scoliosis and in patients with idiopathic scoliosis. J Pediatr Orthop 14:329–335PubMedCrossRefGoogle Scholar
  12. 12.
    Machida M, Dubousset J, Satoh T et al (2001) Pathologic mechanism of experimental scoliosis in pinealectomized chickens. Spine (Phila Pa 1976) 26:E385–E391CrossRefGoogle Scholar
  13. 13.
    Turgut M, Yenisey C, Uysal A, Bozkurt M, Yurtseven ME (2003) The effects of pineal gland transplantation on the production of spinal deformity and serum melatonin level following pinealectomy in the chicken. Eur Spine J 12:487–494PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Turhan E, Acaroglu E, Bozkurt G, Alanay A, Yazici M, Surat A (2006) Unilateral enucleation affects the laterality but not the incidence of scoliosis in pinealectomized chicken. Spine (Phila Pa 1976) 31:133–138CrossRefGoogle Scholar
  15. 15.
    Bagnall K, Raso VJ, Moreau M, Mahood J, Wang X, Zhao J (1999) The effects of melatonin therapy on the development of scoliosis after pinealectomy in the chicken. J Bone Joint Surg Am 81:191–199PubMedGoogle Scholar
  16. 16.
    Bagnall KM, Beuerlein M, Johnson P, Wilson J, Raso VJ, Moreau M (2001) Pineal transplantation after pinealectomy in young chickens has no effect on the development of scoliosis. Spine (Phila Pa 1976) 26:1022–1027CrossRefGoogle Scholar
  17. 17.
    Akel I, Kocak O, Bozkurt G, Alanay A, Marcucio R, Acaroglu E (2009) The effect of calmodulin antagonists on experimental scoliosis: a pinealectomized chicken model. Spine (Phila Pa 1976) 34:533–538CrossRefGoogle Scholar
  18. 18.
    Machida M, Dubousset J, Yamada T et al (2006) Experimental scoliosis in melatonin-deficient C57BL/6J mice without pinealectomy. J Pineal Res 41:1–7PubMedCrossRefGoogle Scholar
  19. 19.
    Akel I, Demirkiran G, Alanay A, Karahan S, Marcucio R, Acaroglu E (2009) The effect of calmodulin antagonists on scoliosis: bipedal C57BL/6 mice model. Eur Spine J 18:499–505PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Francucci CM, Romagni P, Boscaro M (2005) Raloxifene: bone and cardiovascular effects. J Endocrinol Invest 28:85–89PubMedGoogle Scholar
  21. 21.
    Vogel VG, Costantino JP, Wickerham DL et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741PubMedCrossRefGoogle Scholar
  22. 22.
    Cano A, Dapia S, Noguera I et al (2008) Comparative effects of 17beta-estradiol, raloxifene and genistein on bone 3D microarchitecture and volumetric bone mineral density in the ovariectomized mice. Osteoporos Int 19:793–800PubMedCrossRefGoogle Scholar
  23. 23.
    Delmas PD, Bjarnason NH, Mitlak BH et al (1997) Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:1641–1647PubMedCrossRefGoogle Scholar
  24. 24.
    Goff CW, Landmesser W (1957) Bipedal rats and mice; laboratory animals for orthopaedic research. J Bone Joint Surg Am 39-A:616–622PubMedGoogle Scholar
  25. 25.
    Machida M, Dubousset J, Yamada T, Kimura J (2009) Serum melatonin levels in adolescent idiopathic scoliosis prediction and prevention for curve progression–a prospective study. J Pineal Res 46:344–348PubMedCrossRefGoogle Scholar
  26. 26.
    Qiu XS, Tang NL, Yeung HY et al (2007) Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 32:1748–1753CrossRefGoogle Scholar
  27. 27.
    Moreau A, Wang DS, Forget S et al (2004) Melatonin signaling dysfunction in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 29:1772–1781CrossRefGoogle Scholar
  28. 28.
    Letellier K, Azeddine B, Parent S, Labelle H, Rompré PH, Moreau A, Moldovan F (2008) Estrogen cross-talk with the melatonin signaling pathway in human osteoblasts derived from adolescent idiopathic scoliosis patients. J Pineal Res 45:383–393PubMedCrossRefGoogle Scholar
  29. 29.
    Cheung WY (1980) Calmodulin plays a pivotal role in cellular regulation. Science 207:19–27PubMedCrossRefGoogle Scholar
  30. 30.
    Xia Z, Storm DR (1997) Calmodulin-regulated adenylyl cyclases and neuromodulation. Curr Opin Neurobiol 7:391–396PubMedCrossRefGoogle Scholar
  31. 31.
    Cheng JC, Guo X, Sher AH (1999) Persistent osteopenia in adolescent idiopathic scoliosis. A longitudinal follow up study. Spine 24 (Phila Pa 1976):1218–1222CrossRefGoogle Scholar
  32. 32.
    Cheng JC, Qin L, Cheung CS et al (2000) Generalized low areal and volumetric bone mineral density in adolescent idiopathic scoliosis. J Bone Miner Res 15:1587–1595PubMedCrossRefGoogle Scholar
  33. 33.
    Chen WJ, Qiu Y, Zhu F et al (2008) Vitamin D receptor gene polymorphisms: no association with low bone mineral density in adolescent idiopathic scoliosis girls. Zhonghua Wai Ke Za Zhi 46:1183–1186PubMedGoogle Scholar
  34. 34.
    Inoue M, Minami S, Nakata Y et al (2002) Association between estrogen receptor gene polymorphisms and curve severity of idiopathic scoliosis. Spine (Phila Pa 1976) 27:2357–2362CrossRefGoogle Scholar
  35. 35.
    Dede O, Akel I, Demirkiran G, Yalcin N, Marcucio R, Acaroglu E (2011) Is decreased bone mineral density associated with development of scoliosis? A bipedal osteopenic rat model. Scoliosis 6:24PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Urbauer, Jeffrey L, Ramona J, Bieber-Urbauer, Carrie E. Jolly (2009) Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance. Georgia Univ Research Foundation Inc, AthensGoogle Scholar
  37. 37.
    Leboeuf D, Letellier K, Alos N, Edery P, Moldovan F (2009) Do estrogens impact adolescent idiopathic scoliosis? Trends Endocrinol Metab 20:147–152PubMedCrossRefGoogle Scholar
  38. 38.
    Acaroglu E, Akel I, Alanay A, Yazici M, Marcucio R (2009) Comparison of the melatonin and calmodulin in paravertebral muscle and platelets of patients with or without adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 34:E659–E663CrossRefGoogle Scholar
  39. 39.
    Machida M, Murai I, Miyashita Y, Dubousset J, Yamada T, Kimura J (1999) Pathogenesis of idiopathic scoliosis. Experimental study in rats. Spine (Phila Pa 1976) 24:1985–1989CrossRefGoogle Scholar
  40. 40.
    Janssen MM, de Wilde RF, Kouwenhoven JW, Castelein RM (2011) Experimental animal models in scoliosis research: a review of the literature. Spine J 11:347–358PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Gokhan Demirkiran
    • 1
  • Ozgur Dede
    • 1
  • Nadir Yalcin
    • 2
  • Ibrahim Akel
    • 3
  • Ralph Marcucio
    • 2
  • Emre Acaroglu
    • 4
  1. 1.Department of Orthopedics and TraumatologyHacettepe UniversityAnkaraTurkey
  2. 2.Department of Orthopedic Surgery, Orthopedic Research LaboratoryUniversity of California San FranciscoSan FranciscoUSA
  3. 3.Kent HospitalIzmirTurkey
  4. 4.Ankara Spine CenterAnkaraTurkey

Personalised recommendations