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Local RANKL gene transfer to the periodontal tissue accelerates orthodontic tooth movement

Abstract

It has been reported that not only selective alveolar-bone resorption, but also receptor activator of nuclear factor kappa B ligand (RANKL) expression is induced on the compressed side of an orthodontically moving tooth. Numerous reports have described the pharmacological acceleration of tooth movement (TM) through the activation of osteoclasts. However, because of rapid flush out by blood circulation, daily systemic administration or daily local injection is needed. Previously, we discovered that every-3-days OPG gene transfer to the periodontal-tissue inhibited RANKL-mediated osteoclastogenesis and diminished experimental TM. Therefore, we hypothesized that local RANKL gene transfer into the periodontal tissue would accelerate TM. The upper first molars of 6-week-old male Wistar rats were moved palatally using fixed orthodontic wires. The inactivated hemagglutinating-virus of Japan (HVJ) envelope vector containing the mouse RANKL expression plasmid was injected periodically into the palatal periodontal tissue of the upper first molars during TM. Local RANKL gene transfer significantly enhanced RANKL expression and osteoclastogenesis in periodontal tissue without any systemic effects. The TM rate was significantly increased in the RANKL gene transfer side. In conclusion, we demonstrated that transfer of the RANKL gene to the periodontal-tissue activated osteoclastogenesis and accelerated the amount of experimental TM. Local RANKL gene transfer might be a useful tool not only for shortening orthodontic treatment, but also for moving ankylosed teeth where teeth, fuse to the surrounding bone.

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References

  1. Roberts WE, Goodwin Jr WC, Heiner SR . Cellular response to orthodontic force. Dent Clin North Am 1981; 25: 3–17.

    CAS  PubMed  Google Scholar 

  2. Mitchell DL, West JD . Attempted orthodontic movement in the presence of suspected ankylosis. Am J Orthod 1975; 68: 404–411.

    Article  CAS  Google Scholar 

  3. Lekic P, McCulloch CA . Periodontal ligament cell populations: The central role of fibroblasts in creating a unique tissue. Anat Rec 1996; 245: 327–341.

    Article  CAS  Google Scholar 

  4. Storey E . The nature of tooth movement. Am J Orthod 1973; 63 (3): 292–314.

    Article  CAS  Google Scholar 

  5. Davidovitch Z, Nicolay OF, Ngan PW, Shanfeld JL . Neurotransmitters, cytokines, and the control of alveolar bone remodeling in orthodontics. Dent Clin North Am 1988; 32: 411–435.

    CAS  PubMed  Google Scholar 

  6. Brudvik P, Rygh P . Multi-nucleated cells remove the main hyalinized tissue and start resorption of adjacent root surfaces. Eur J Orthod 1994; 16 (4): 265–273.

    Article  CAS  Google Scholar 

  7. Udagawa N, Takahashi N, Jimi E, Matsuzaki K, Tsurukai T, Itoh K et al. Osteoblasts/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor. Bone 1999; 25: 517–523.

    Article  CAS  Google Scholar 

  8. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Goto M et al. A novel molecular mechanism modulating osteoclast differentiation and function. Bone 1999; 25: 109–113.

    Article  CAS  Google Scholar 

  9. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R et al. Osteoprotegerin: A novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309–319.

    Article  CAS  Google Scholar 

  10. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ, Riggs BL . The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000; 15 (1): 2–12.

    Article  CAS  Google Scholar 

  11. Oshiro T, Shiotani A, Shibasaki Y, Sasaki T . Osteoclast Induction in Periodontal Tissue During Experimental Movement of Incisors in Osteoprotegerin-Deficient Mice. Anat Rec 2002; 266: 218–225.

    Article  Google Scholar 

  12. Collins MK, Sinclair PM . The local use of vitamin D to increase the rate of orthodontic tooth movement. Am J Orthod Dentofacial Orthop 1988; 94: 278–284.

    Article  CAS  Google Scholar 

  13. Lee WC . Experimental study of the effect of prostaglandin administration on tooth movement--with particular emphasis on the relationship to the method of PGE1 administration. Am J Orthod Dentofacial Orthop 1990; 98 (3): 231–241.

    Article  CAS  Google Scholar 

  14. Hashimoto F, Kobayashi Y, Mataki S, Kobayashi K, Kato Y, Sakai H . Administration of osteocalcin accelerates orthodontic tooth movement induced by a closed coil spring in rats. Eur J Orthod 2001; 23 (5): 535–545.

    Article  CAS  Google Scholar 

  15. Soma S, Matsumoto S, Higuchi Y, Takano-Yamamoto T, Yamashita K, Kurisu K et al. Local and chronic application of PTH accelerates tooth movement in rats. J Dent Res 2000; 79: 1717–1724.

    Article  CAS  Google Scholar 

  16. Kanzaki H, Chiba M, Takahashi I, Haruyama N, Nishimura M, Mitani H . Local OPG gene transfer to the periodontal tissue inhibits orthodontic tooth movement. J Dent Res 2004; 83 (12): 920–925.

    Article  CAS  Google Scholar 

  17. Saitoh S, Takahashi I, Mizoguchi I, Sasano Y, Kagayama M, Mitani H . Compressive force promotes chondrogenic differentiation and hypertrophy in midpalatal suture cartilage in growing rats. Anat Rec 2000; 260: 392–401.

    Article  CAS  Google Scholar 

  18. Kaneda Y, Nakajima T, Nishikawa T, Yamamoto S, Ikegami H, Suzuki N et al. Hemagglutinating Virus of Japan (HVJ) Envelope Vector as a Versatile Gene Delivery System. Mol Ther 2002; 6 (2): 219–226.

    Article  CAS  Google Scholar 

  19. Tsuboniwa N, Morishita R, Hirano T, Fujimoto J, Furukawa S, Kikumori M et al. Safety evaluation of hemagglutinating virus of Japan-artificial viral envelope liposomes in nonhuman primates. Hum Gene Ther 2001; 12 (5): 469–487.

    Article  CAS  Google Scholar 

  20. Ogasawara T, Yoshimine Y, Kiyoshima T, Kobayashi I, Matsuo K, Akamine A et al. In situ expression of RANKL, RANK, osteoprotegerin and cytokines in osteoclasts of rat periodontal tissue. J Periodont Res 2004; 39: 42–49.

    Article  CAS  Google Scholar 

  21. Oshiro T, Shiotani A, Shibasaki Y, Sasaki T . Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin-deficient mice. Anat Rec 2002; 266 (4): 218–225.

    Article  Google Scholar 

  22. Sasaki T . Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorption. Microsc Res Tech 2003; 61: 483–495.

    Article  CAS  Google Scholar 

  23. Fukushima H, Kajiya H, Takada K, Okamoto F, Okabe K . Expression and role of RANKL in periodontal ligament cells during physiological root-resorption in human deciduous teeth. Eur J Oral Sci 2003; 111: 346–352.

    Article  CAS  Google Scholar 

  24. Hasegawa T, Yoshimura Y, Kikuiri T, Yawaka Y, Takeyama S, Matsumoto A et al. Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells. J Periodont Res 2002; 37: 405–411.

    Article  CAS  Google Scholar 

  25. Kanzaki H, Chiba M, Shimizu Y, Mitani H . Periodontal Ligament Cells Under Mechanical Stress Induce Osteoclastogenesis by Receptor Activator of Nuclear Factor kappa B Ligand Up-Regulation via Prostaglandin E2 Synthesis. J Bone Miner Res 2002; 17: 210–220.

    Article  CAS  Google Scholar 

  26. Blesing CH, Kerr DJ . Intra-hepatic arterial drug delivery. J Drug Target 1996; 3 (5): 341–347.

    Article  CAS  Google Scholar 

  27. Bolon B, Carter C, Daris M, Morony S, Capparelli C, Hsieh A et al. Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis. Mol Ther 2001; 3 (2): 197–205.

    Article  CAS  Google Scholar 

  28. Goater JJ, O’Keefe RJ, Rosier RN, Puzas JE, Schwarz EM . Efficacy of ex vivo OPG gene therapy in preventing wear debris induced osteolysis. J Orthop Res 2002; 20 (2): 169–173.

    Article  CAS  Google Scholar 

  29. Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J et al. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med 2005; 11 (3): 291–297.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (12671984, 16390602).

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Correspondence to H Kanzaki.

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Kanzaki, H., Chiba, M., Arai, K. et al. Local RANKL gene transfer to the periodontal tissue accelerates orthodontic tooth movement. Gene Ther 13, 678–685 (2006). https://doi.org/10.1038/sj.gt.3302707

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