Abstract
Bisphosphonate-induced osteonecrosis of the jaw (BIONJ) is a commonly encountered side effect of Bisphosphonates (BPs). Although certain aspects of BIONJ have been studied, the effects of BPs on the proliferation, differentiation, and maintenance of dental stem cells (DSC) in way that might account for development of BIONJ have not been evaluated. In the current study, Dental Pulp Stem Cells (DPSCs), Periodontal Stem Cells (PDLSCs), and human Tooth Germ Stem Cells (hTGSCs) were characterized and then each stem cell type were treated with selected BPs: Zoledronate (ZOL), Alendronate (ALE), and Risedronate (RIS). Negative effect on osteogenesis capacity of DSCs has not been observed after differentiation experiments in vitro. BPs exerted inhibitory effect on the migratory capacities of stem cells confirmed by in vitro scratch assay analysis. Angiogenesis of endothelial cells was blocked by BPs treatment in tube formation analysis. In conclusion, inhibitory effects of BPs on migration capacity of DSCs localized in close proximity to the jaw bone might be the primary reason for the side effects of BPs in the development of BIONJ process. Therefore, further in vivo evidence is required to investigate DSC properties in BP treated animals which might elucidate the importance of DSCs in BIONJ formation.
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References
Blau HM, Brazelton T, Weimann J (2001) The evolving concept of a stem cell: entity or function? Cell 105:829–841
Henningson CT Jr, Stanislaus MA, Gewirtz AM (2003) 28. Embryonic and adult stem cell therapy. J Allergy Clin Immunol 111:S745–S753
Egusa H, Sonoyama W, Nishimura M, Atsuta I, Akiyama K (2012) Stem cells in dentistry–part I: stem cell sources. J Prosthodont Res 56:151–165
Alge DL, Zhou D, Adams LL et al (2010) Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Regener Med 4:73–81
Ito K, Yamada Y, Nakamura S, Ueda M (2011) Osteogenic potential of effective bone engineering using dental pulp stem cells, bone marrow stem cells, and periosteal cells for osseointegration of dental implants. Int J Oral Maxillofac Implant 26:5
Seo B-M, Miura M, Gronthos S et al (2004) Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364:149–155
Deal C (2009) Potential new drug targets for osteoporosis. Nat Rev Rheumatol 5:20
Reid D (2011) Handbook of osteoporosis. Springer, Berlin
Hacchou Y, Uematsu T, Ueda O et al (2007) Inorganic polyphosphate: a possible stimulant of bone formation. J Dental Res 86:893–897
Hosseini FS, Soleimanifar F, Khojasteh A, Ardeshirylajimi A (2018) Promoting osteogenic differentiation of human-induced pluripotent stem cells by releasing Wnt/β-catenin signaling activator from the nanofibers. J Cell Biochem
Rogers M, Frith J, Luckman S et al (1999) Molecular mechanisms of action of bisphosphonates. Bone 24:73S–73S9S
Russell RGG (2007) Bisphosphonates: mode of action and pharmacology. Pediatrics 119:S150–S162
Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s–6222s30 s
De Ponte FS (2012) Bisphosphonates and osteonecrosis of the jaw: a multidisciplinary approach. Springer, Berlin
Marini F, Brandi ML (2014) Pharmacogenetics of osteoporosis. Best Pract Res Clin Endocrinol Metab, 28, 783–93
Santini D, Vincenzi B, Avvisati G et al (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8:1080–1084
Wood J, Bonjean K, Ruetz S et al (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061
Ogose A, Motoyama T, Hotta T, Watanabe H (1996) Expression of bone morphogenetic proteins in human osteogenic and epithelial tumor cells. Pathol Int 46:9–14
Xuan K, Jin F, Liu Y-L et al (2008) Identification of a novel missense mutation of MSX1 gene in Chinese family with autosomal-dominant oligodontia. Arch Oral Biol 53:773–779
Nam S, Won J-E, Kim C-H, Kim H-W (2011) Odontogenic differentiation of human dental pulp stem cells stimulated by the calcium phosphate porous granules. J Tissue Eng 2011:812547
Doğan A, Yalvaç ME, Şahin F, Kabanov AV, Palotás A, Rizvanov AA (2012) Differentiation of human stem cells is promoted by amphiphilic pluronic block copolymers. Int J Nanomed 7:4849
Ding X, Zhou L, Wang J et al (2015) The effects of hierarchical micro/nanosurfaces decorated with TiO2 nanotubes on the bioactivity of titanium implants in vitro and in vivo. Int J Nanomed 10:6955
Taşlı PN, Aydın S, Yalvaç ME, Şahin F (2014) Bmp 2 and bmp 7 induce odonto-and osteogenesis of human tooth germ stem cells. Appl Biochem Biotechnol 172:3016–3025
Doğan A, Demirci S, Apdik H, Apdik EA, Şahin F (2017) Dental pulp stem cells (DPSCs) increase prostate cancer cell proliferation and migration under in vitro conditions. Tissue Cell 49:711–718
Lisignoli G, Cristino S, Piacentini A et al (2005) Cellular and molecular events during chondrogenesis of human mesenchymal stromal cells grown in a three-dimensional hyaluronan based scaffold. Biomaterials 26:5677–5686
Woo S-B, Hellstein JW, Kalmar JR (2006) Systematic review: bisphosphonates and osteonecrosis of the jaws. Ann Internal Med 144:753–761
Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347
Marchionni C, Bonsi L, Alviano F et al (2009) Angiogenic potential of human dental pulp stromal (stem) cells. Int J Immunopathol Pharmacol 22:699–706
Yu J, Wang Y, Deng Z et al (2007) Odontogenic capability: bone marrow stromal stem cells versus dental pulp stem cells. Biol Cell 99:465–474
Saoji NA (2008) Effect of bisphosphonate on osteogenic differentiation of pulp and PDL Cells. University of Alabama at Birmingham, Birmingham
Casado-Díaz A, Santiago-Mora R, Dorado G, Quesada-Gómez JM (2013) Risedronate positively affects osteogenic differentiation of human mesenchymal stromal cells. Arch Med Res 44:325–334
Duque G, Rivas D (2007) Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res 22:1603–1611
von Knoch F, Jaquiery C, Kowalsky M et al (2005) Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells. Biomaterials 26:6941–6949
Ruggiero SL (2007) Guidelines for the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Clin Cases Min Bone Metabol 4, 37
Zhang Z, Liu W, Zheng Y, Jin L, Yao W, Gao X (2014) SGP-2, an acidic polysaccharide from Sarcandra glabra, inhibits proliferation and migration of human osteosarcoma cells. Food Function 5, 167–75
Pourgonabadi S, Ghorbani A, Mousavi SH (2018) In vitro assessment of alendronate toxic and apoptotic effects on human dental pulp stem cells. Iran J Basic Med Sci 21:905–910
Sharma D, Hamlet SM, Petcu EB, Ivanovski S (2016) The effect of bisphosphonates on the endothelial differentiation of mesenchymal stem cells. Sci Rep 6:20580
Shiomi K, Nagata Y, Kiyono T, Harada A, Hashimoto N (2014) Differential impact of the B isphosphonate A lendronate on undifferentiated and terminally differentiated human myogenic cells. J Pharm Pharmacol 66:418–427
Berrier AL, Yamada KM (2007) Cell–matrix adhesion. J Cell Physiol 213:565–573
Shiba H, Fujita T, Doi N et al (1998) Differential effects of various growth factors and cytokines on the syntheses of DNA, type I collagen, laminin, fibronectin, osteonectin/secreted protein, acidic and rich in cysteine (SPARC), and alkaline phosphatase by human pulp cells in culture. J Cell Physiol 174:194–205
Tabata MJ, Matsumura T, Fujii T, Abe M, Kurisu K (2003) Fibronectin accelerates the growth and differentiation of ameloblast lineage cells in vitro. J Histochem Cytochem 51:1673–1679
Yuasa K, Fukumoto S, Kamasaki Y et al (2004) Laminin α2 is essential for odontoblast differentiation regulating dentin sialoprotein expression. J Biol Chem 279:10286–10292
Yang X, Zhang S, Pang X, Fan M (2012) Retraction: Pro-inflammatory cytokines induce odontogenic differentiation of dental pulp-derived stem cells. J Cell Biochem 113:2796-
Boomsma RA, Geenen DL (2012) Mesenchymal stem cells secrete multiple cytokines that promote angiogenesis and have contrasting effects on chemotaxis and apoptosis. PLoS ONE 7:e35685
Li Y, Yu X, Lin S, Li X, Zhang S, Song Y-H (2007) Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells. Biochem Biophys Res Commun 356:780–784
Ponte AL, Marais E, Gallay N et al (2007) The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem cells 25:1737–1745
Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta (BBA) 1803:55–71
Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P (2007) MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109:4055–4063
Granero-Moltó F, Myers TJ, Weis JA et al (2011) Mesenchymal stem cells expressing insulin-like growth factor-I (MSCIGF) promote fracture healing and restore new bone formation in Irs1 knockout mice: analyses of MSCIGF autocrine and paracrine regenerative effects. Stem Cells 29:1537–1548
Acknowledgements
This study was supported by Yeditepe University. The authors would like to thank Dr. Neslihan Taşlı for her guidance during the experimental stages and Dr. Aslı Hızlı Deniz for her assistance during writing stages.
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Abdik, H., Avşar Abdik, E., Demirci, S. et al. The effects of bisphosphonates on osteonecrosis of jaw bone: a stem cell perspective. Mol Biol Rep 46, 763–776 (2019). https://doi.org/10.1007/s11033-018-4532-x
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DOI: https://doi.org/10.1007/s11033-018-4532-x