Effects of Bisphosphonates on the Proliferation and the AlkalinePhosphatase Activity of Human Bone Marrow Derived Mesenchymal Stem Cells

Bisphosphonate가 인간 골수유래 간엽줄기세포의 증식과 알칼리성 인산분해효소 활성에 미치는 영향

  • Jung, Jun-Ho (Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung-Hee University) ;
  • Lee, Baek-Soo (Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung-Hee University) ;
  • Kwon, Yong-Dae (Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung-Hee University) ;
  • Ohe, Joo-Young (Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung-Hee University) ;
  • Kim, Young-Ran (Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung-Hee University)
  • 정준호 (경희대학교 치의학전문대학원 구강악안면외과학교실) ;
  • 이백수 (경희대학교 치의학전문대학원 구강악안면외과학교실) ;
  • 권용대 (경희대학교 치의학전문대학원 구강악안면외과학교실) ;
  • 오주영 (경희대학교 치의학전문대학원 구강악안면외과학교실) ;
  • 김영란 (경희대학교 치의학전문대학원 구강악안면외과학교실)
  • Received : 2010.10.27
  • Accepted : 2010.11.11
  • Published : 2011.01.31

Abstract

Purpose: The purpose of this study is to find out the effects of bisphosphonates (BPs) on the proliferation and the alkaline phosphatase (ALP) activity of human bone marrow derived mesenchymal stem cells (hMSCs), and thus state its correlation with bisphosphonate related osteonecrosis of the jaw (BRONJ). Methods: hMSCs was obtained by collecting and culturing cancellous bone fragments from a patient undergoing iliac bone graft. Alendronate (Aln) and Pamidronate (Pam), Ibandronate (Ibn) were added to the culture media in the concentration from $10^{-3}$ M to $10^{-11}$ M and cell toxicity, viability were measured. For ALP activity evaluation, Aln and Pam were added to the culture media in the concentration from $5{\times}10^{-7}$ M to $1{\times}10^{-8}$ M and were cultured for 1 week, 2 weeks and 3 weeks. ALP activity data were standardized using protein assay. Control groups were prepared for each examination. Results: Aln, Pam and Ibn all failed to increase the proliferation of hMSCs. With 1 week, 2 weeks of $5{\times}10^{-8}$M of Aln treatment, the ALP activity increased. Pam treatment increased the ALP activity with 2 weeks of $5{\times}10^{-8}$ M and$1{\times}10^{-8}$M. Also Ibn treatment increased the ALP activity with 2 weeks of $5{\times}10^{-8}$ M and $1{\times}10^{-8}$ M. Conclusion: It is considered that BPs are not capable of improving the proliferation of hMSCs. Also, after a transient increase in the ALP activity with the lower concentration of BPs, the activity decreased again. Therefore, in patients on long-term medication of BPs, the proliferation and osteoblast differentiation of hMSCs are restrained, and thus delayed wound healing and increase in BRONJ complications may occur.

Keywords

References

  1. Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science 2000;289:1508-14. https://doi.org/10.1126/science.289.5484.1508
  2. Pataki A, Muller K, Green JR, Ma YF, Li QN, Jee WS. Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment. Anat Rec 1997;249:458-68. https://doi.org/10.1002/(SICI)1097-0185(199712)249:4<458::AID-AR5>3.0.CO;2-N
  3. Gasser AB, Morgan DB, Fleisch HA, Richelle LJ. The influence of two diphosphonates on calcium metabolism in the rat. Clin Sci 1972;43:31-45. https://doi.org/10.1042/cs0430031
  4. Balena R, Toolan BC, Shea M, et al. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 1993;92:2577-86. https://doi.org/10.1172/JCI116872
  5. Walsh JP, Ward LC, Stewart GO, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone 2004;34:747-54. https://doi.org/10.1016/j.bone.2003.12.011
  6. Wellington K, Goa KL. Zoledronic acid: a review of its use in the management of bone metastases and hypercalcaemia of malignancy. Drugs 2003;63:417-37. https://doi.org/10.2165/00003495-200363040-00009
  7. Lane JM, Khan SN, O'Connor WJ, et al. Bisphosphonate therapy in fibrous dysplasia. Clin Orthop Relat Res 2001; (382):6-12.
  8. Devogelaer JP. New uses of bisphosphonates: osteogenesis imperfecta. Curr Opin Pharmacol 2002;2:748-53. https://doi.org/10.1016/S1471-4892(02)00218-7
  9. Lehmann HJ, Mouritzen U, Christgau S, Cloos PA, Christiansen C. Effect of bisphosphonates on cartilage turnover assessed with a newly developed assay for collagen type II degradation products. Ann Rheum Dis 2002;61: 530-3. https://doi.org/10.1136/ard.61.6.530
  10. Cremers S, Sparidans R, den HJ, Hamdy N, Vermeij P, Papapoulos S. A pharmacokinetic and pharmacodynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis. Eur J Clin Pharmacol 2002;57:883-90. https://doi.org/10.1007/s00228-001-0411-8
  11. Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-99. https://doi.org/10.1056/NEJMoa030897
  12. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34. https://doi.org/10.1016/j.joms.2004.02.004
  13. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate- induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567-75. https://doi.org/10.1016/j.joms.2005.07.010
  14. Migliorati CA, Siegel MA, Elting LS. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 2006;7:508-14. https://doi.org/10.1016/S1470-2045(06)70726-4
  15. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61:1115-7. https://doi.org/10.1016/S0278-2391(03)00720-1
  16. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19:80-100. https://doi.org/10.1210/er.19.1.80
  17. Schenk R, Merz WA, Mühlbauer R, Russell RG, Fleisch H. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res 1973;11:196-214. https://doi.org/10.1007/BF02547219
  18. Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res 1973;11:269-80. https://doi.org/10.1007/BF02547227
  19. Marx RE. Bisphosphonate-induced osteonecrosis of the jaws: a challenge, a responsibility, and an opportunity. Int J Periodontics Restorative Dent 2008;28:5-6.
  20. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003;9:2643-58. https://doi.org/10.2174/1381612033453640
  21. Fisher JE, Rogers MJ, Halasy JM, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Proc Natl Acad Sci U S A 1999;96:133-8. https://doi.org/10.1073/pnas.96.1.133
  22. Hughes DE, MacDonald BR, Russell RG, Gowen M. Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest 1989;83:1930-5. https://doi.org/10.1172/JCI114100
  23. Lowik CW, van der Pluijm G, van der Wee-Pals LJ, van Treslong-De Groot HB, Bijvoet OL. Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts: the effect of a bisphosphonate. J Bone Miner Res 1988;3:185-92.
  24. Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10:1478-87.
  25. Mathov I, Plotkin LI, Sgarlata CL, Leoni J, Bellido T. Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro. J Bone Miner Res 2001;16: 2050-6. https://doi.org/10.1359/jbmr.2001.16.11.2050
  26. Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G. Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 1998;22:455-61. https://doi.org/10.1016/S8756-3282(98)00033-7
  27. 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;104:1363-74. https://doi.org/10.1172/JCI6800
  28. Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 2004;25:4105-15. https://doi.org/10.1016/j.biomaterials.2003.11.024
  29. Reinholz GG, Getz B, Pederson L, et al. Bisphosphonates directly regulate cell proliferation, differentiation, and gene expression in human osteoblasts. Cancer Res 2000;60:6001-7.
  30. 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;68:186-94. https://doi.org/10.1002/(SICI)1097-4644(19980201)68:2<186::AID-JCB5>3.0.CO;2-R
  31. Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res 2007;22:1603-11. https://doi.org/10.1359/jbmr.070701
  32. Qiao C, Xu W, Zhu W, et al. Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int 2008;32: 8-15. https://doi.org/10.1016/j.cellbi.2007.08.002
  33. Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991;88:2095-105. https://doi.org/10.1172/JCI115539
  34. Fromigue O, Body JJ. Bisphosphonates influence the proliferation and the maturation of normal human osteoblasts. J Endocrinol Invest 2002;25:539-46. https://doi.org/10.1007/BF03345497
  35. Garcia-Moreno C, Serrano S, Nacher M, et al. Effect of alendronate on cultured normal human osteoblasts. Bone 1998;22:233-9. https://doi.org/10.1016/S8756-3282(97)00270-6
  36. von Knoch F, Jaquiery C, Kowalsky M, et al. Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials 2005;26: 6941-9. https://doi.org/10.1016/j.biomaterials.2005.04.059
  37. Still K, Phipps RJ, Scutt A. Effects of risedronate, alendronate, and etidronate on the viability and activity of rat bone marrow stromal cells in vitro. Calcif Tissue Int 2003;72: 143-50. https://doi.org/10.1007/s00223-001-2066-y
  38. 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;91:2004-11. https://doi.org/10.1172/JCI116422
  39. Stefanik D, Sarin J, Lam T, Levin L, Leboy PS, Akintoye SO. Disparate osteogenic response of mandible and iliac crest bone marrow stromal cells to pamidronate. Oral Dis 2008; 14:465-71. https://doi.org/10.1111/j.1601-0825.2007.01402.x
  40. Kim YR, Ryu DM, Kwon YD, Yun YP. Effects of alendronate and pamidronate on the proliferation and the alkaline phosphatase activity of human bone marrow derived mesenchymal stem cells. J Korean Oral Maxillofac Surg 2009;35: 397-402.
  41. Fu L, Tang T, Miao Y, Zhang S, Qu Z, Dai K. Stimulation of osteogenic differentiation and inhibition of adipogenic differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone 2008;43:40-7. https://doi.org/10.1016/j.bone.2008.03.008
  42. Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG. Clinical pharmacology of alendronate sodium. Osteoporos Int 1993;3(Suppl 3):S13-6.