Altered Expression of RANKL/OPG after Alendronate Administration in the Developing Teeth of Postnatal Rats

  • Kim, Min-Ju (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Jun, Yun-Jeong (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Yu, Hong-Il (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Yang, So-Yeong (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Oh, Won-Man (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Kim, Sun-Hun (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University) ;
  • Kim, Min-Seok (Dental Science Research Institute, 2nd Stage Brain Korea, School of Dentistry, Chonnam National University)
  • Received : 2011.01.12
  • Accepted : 2011.03.04
  • Published : 2011.03.31

Abstract

The working mechanism of bisphosphonate on bone cells is unclear despite its powerful inhibitory activity on bone resorption. The differentiation and activation of osteoclasts are essential for bone resorption and are controlled by the stimulatory RANKL and inhibitory OPG molecules. Teeth exhibit a range of movement patterns during their eruption to establish their form and function, which inevitably accompanies peripheral bone resorption. Hence, the mandible, which contains the teeth during their eruption processes, is a good model for revealing the inhibitory mechanism of bisphosphonate upon bone resorption. In the present study, RANKL and OPG expression were examined immunohistochemically in the mandible of rats with developing teeth after alendronate administration (2.5 mg/kg). The preeruptive mandibular first molars at postnatal days 3 to 10 showed the developing stages from bell to crown. No morphological changes in tooth formation were observed after alendronate administration. The number of osteoclasts in the alveolar bone around the developing teeth decreased markedly at postnatal days 3, 7 and 10 compared with the control group. RANKL induced strong positive immunohistochemical reactions in the dental follicles and stromal cells around the mandibular first molar. In particular, many osteoclasts with strongly positive reactions to RANKL appeared above the developing mandibular first molars at postnatal days 3 and 10. Immunohistochemical reactions with RANKL after alendronate administration were weaker than the control groups. However, the immunohistochemical reactivity to OPG was stronger after alendronate administration, at postnatal days 3 and 10. These results suggest that alendronate may decrease bone resorption by regulating the RANKL/OPG pathway in the process of osteoclast formation, resulting in a delay in tooth eruption.

Keywords

References

  1. Fleisch H. Bisphosphonates in bone disease: From the laboratory to the patient 3rd Ed. 1997.
  2. Hughes DE, MacDonald BR, Russell RG, Gowen M. Inhibition of osteoclast-like cell formation by bisphosphonates in longterm cultures of human bone marrow. J Clin Invest. 1989;83(6):1930-5. https://doi.org/10.1172/JCI114100
  3. 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. https://doi.org/10.1359/jbmr.2000.15.1.2
  4. Jeong HJ, Yushun T, Kim BH, Nam MY, Lee HA, Yoo YJ, Seo JT, Shin DM, Ohk SH, Lee SI. Hypertonicity Down-regulates the 1$\alpha$,25(OH)2Vitamin D3-induced Osteoclastogenesis Via the Modulation of RANKL Expression in Osteoblast. Int J Oral Biol. 2005;30(1);23-30.
  5. Jilka RL, Takahashi K, Munshi M, Williams DC, Roberson PK, Manolagas SC. Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption. J Clin Invest. 1998;101(9):1942-50. https://doi.org/10.1172/JCI1039
  6. Kawata T, Tenjou K, Tokimasa C, Fujita T, Kaku M, Matsuki A, Kohno S, Tsutsui K, Ohtani J, Motokawa M, Shigekawa M, Tohma Y, Tanne K. Effect of alendronate on osteoclast differentiation and bone volume in transplanted bone. Exp Anim. 2004;53(1):47-51. https://doi.org/10.1538/expanim.53.47
  7. Kim YH, Kim GS, Jeong-Hwa B. Inhibitory action of bisphosphonates on bone resorption does not involve the regulation of RANKL and OPG expression. Exp Mol Med. 2002; 34(2):145-51. https://doi.org/10.1038/emm.2002.21
  8. Klein BY, Ben-Bassat H, Breuer E, Solomon V, Golomb G. Structurally different bisphosphonates exert opposing effects on alkaline phosphatase and mineralization in marrow osteoprogenitors. J Cell Biochem. 1998;68(2):186-94. https://doi.org/10.1002/(SICI)1097-4644(19980201)68:2<186::AID-JCB5>3.0.CO;2-R
  9. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998; 93(2):165-76. https://doi.org/10.1016/S0092-8674(00)81569-X
  10. Mackie PS, Fisher JL, Zhou H, Choong PF. Bisphosphonates regulate cell growth and gene expression in the UMR 106-01 clonal rat osteosarcoma cell line. Br J Cancer. 2001;84(7):951-8. https://doi.org/10.1054/bjoc.2000.1679
  11. Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000;343(9):604-10. https://doi.org/10.1056/NEJM200008313430902
  12. Papoulous S. Bisphosphonates: Pharmacology and use in the treatment of osteoporosis. In Osteoporosis. pp. 1209-34. 1996.
  13. Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF. A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res. 1996;11(2):150-9.
  14. Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest. 1999;104(10):1363-74. https://doi.org/10.1172/JCI6800
  15. Reinholz GG, Getz B, Pederson L, Sanders ES, Subramaniam M, Ingle. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res. 2000;60(21):6001-7.
  16. Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309-19. https://doi.org/10.1016/S0092-8674(00)80209-3
  17. Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88(12 Suppl):2961-78. https://doi.org/10.1002/1097-0142(20000615)88:12+<2961::AID-CNCR12>3.0.CO;2-L
  18. Roodman GD. Advances in bone biology: the osteoclast. End Rev. 1996;17:308-22.
  19. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, Thamsborg G, Liberman UA, Delmas PD, Malice MP, Czachur M, Daifotis AG. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med. 1998;339(5):292-9. https://doi.org/10.1056/NEJM199807303390502
  20. Sahni M, Guenther HL, Fleisch H, Collin P, Martin TJ. Bisphosphonates act on rat bone resorption through the mediation of osteoblasts. J Clin Invest. 1993;91(5):2004-11. https://doi.org/10.1172/JCI116422
  21. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Boyle WJ et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309-19. https://doi.org/10.1016/S0092-8674(00)80209-3
  22. Shin JY, Baek DH, Han SB. The Effects of Sex Hormones on the Expression of ODF/OPG in Human Gingival Fibroblast and Periodontal Ligament Cell at Serum Concentration During Pregnancy. Int J Oral Biol. 2005;30(3):105-110.
  23. Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function. J Bone Miner Res. 1997; 2(6):869-79.
  24. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20(3):345-57. https://doi.org/10.1210/er.20.3.345
  25. Vitte C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology. 1996;137(6):2324-33. https://doi.org/10.1210/en.137.6.2324
  26. Wise GE, Lin F. The molecular biology of initiation of tooth eruption. J Dent Res. 1995; 74(1):303-6. https://doi.org/10.1177/00220345950740010301
  27. Wise GE, Huang H, Que BG. Gene expression of potential tooth eruption molecules in the dental follicle of the mouse. Eur J Oral Sci. 1999;107(6):482-6. https://doi.org/10.1046/j.0909-8836.1999.eos107610.x
  28. Wise GE, Yao S, Zhang Q, Ren Y. Inhibition of osteoclastogenesis by the secretion of osteoprotegerin in vitro by rat dental follicle cells and its implications for tooth eruption. Arch Oral Biol. 2002a;47(3):247-54. https://doi.org/10.1016/S0003-9969(01)00109-1
  29. Wise GE, Frazier-Bowers S, D'Souza RN. Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med. 2002b;13(4):323-34. https://doi.org/10.1177/154411130201300403
  30. Wise GE, Yao S. Expression of vascular endothelial growth factor in the dental follicle. Crit Rev Eukaryot Gene Expr. 2003;13(2-4):173-80. https://doi.org/10.1615/CritRevEukaryotGeneExpr.v13.i24.90
  31. Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998;95(7):3597-602. https://doi.org/10.1073/pnas.95.7.3597