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Effects of the prevention of medication-related osteonecrosis of the jaw by local administration of a dental pulp stem cell-conditioned medium to the rat tooth extraction socket

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Abstract

The onset of osteonecrosis of the jaw, which is a side effect of bisphosphonates, often develops after tooth extraction; measures for its prevention have not yet been established. While treatment with systemic administration of bone marrow stem cell-derived conditioned medium for medication-related osteonecrosis of the jaw (MRONJ) has been reported, its preventive effects have not been clarified yet, and the high degree of invasiveness of bone marrow fluid collection remains an issue. Therefore, we created a rat model of MRONJ using BP zoledronic acid, used a dental pulp stem cell-conditioned medium (DPSC-CM), which can be collected relatively easily, and locally applied it to the tooth extraction socket with atelocollagen and gelatin sponges. The preventive effect on the onset of MRONJ was subsequently examined. The results demonstrated that the bone exposure width of the extraction socket was reduced, and the mucosal covering was promoted in the atelocollagen + DPSC-CM group as compared with the other groups. Furthermore, histological results indicated a decrease in the number of empty bone lacunae, whereas immunohistochemical staining revealed the presence of many vascular endothelial growth factor (VEGF)-positive cells. Moreover, the results of the investigation of the sustained release of atelocollagen using VEGF indicated the release of VEGF over time. Our results suggest that local administration of DPSC-CM using atelocollagen may be a useful method for the prevention of MRONJ triggered by tooth extraction.

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References

  1. Jang HW, Kim JW, Cha IH. Development of animal model for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Maxillofac Plastic Reconstruct Surg. 2015;37:18.

    Article  Google Scholar 

  2. Kobayashi Y, Hiraga T, Ueda A, Wang L, Matsumoto-Nakano M, Hata K, Yatani H, Yoneda T. Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab. 2010;28:165–75.

    Article  Google Scholar 

  3. Tezuka R, Tanaka A. Jawbone changes in sodium zoledronic acid and dexamethasone-treated rats. J Hard Tissue Biol. 2016;25:383–94.

    Article  Google Scholar 

  4. Sumi K, Abe T, Kunimatsu R, Oki N, Tsuka Y, Awada T, Nakajima K, Ando K, Tanimoto K. The effect of mesenchymal stem cells on chemotaxis of osteoclast precursor cells. J Oral Sci. 2018;60:221–5.

    Article  Google Scholar 

  5. Ogata K, Katagiri W, Osugi M, Kawai T, Sugimura Y, Hibi H, Nakamura S, Ueda M. Evaluation of the therapeutic effects of conditioned media from mesenchymal stem cells in a rat bisphosphonate-related osteonecrosis of the jaw-like model. Bone. 2015;74:95–105.

    Article  Google Scholar 

  6. Sasso RC, LeHuec JC, Shaffrey C, Spine Interbody Research Group. Iliac crest bone graft donor site pain after anterior lumbar interbody fusion: a prospective patient satisfaction outcome assessment. J Spinal Disord Tech. 2005; 18: 77–81.

  7. Sato M, Ishidai S, Iwasa S, Takei H. Characterization of cultured human mesenchymal stem cells from deciduous and permanent teeth. Jap J Pedodont. 2014;52:417–24.

    Google Scholar 

  8. Abe F, Takahashi H, Tanaka A. Investigation on the action and effect of culture supernatant of human dental pulp stem cells using rats with medication-related osteonecrosis of the jaw. J Hard Tissue Biol. 2019;28:349–58.

    Article  Google Scholar 

  9. Bronckaers A, Hilkens P, Fanton Y, Struys T, Gervois P, Politis C, Martens W, Lambrichts I. Angiogenic properties of human dental pulp stem cells. PLoS ONE. 2013;8:e71104.

    Article  Google Scholar 

  10. Doppelt O, Cohen G, Tamari T, Elimekech R, Sabbah N, Zigdon-Giladi H. Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication-related osteonecrosis of the jaw. Oral Dis. 2020;26:1.

    Article  Google Scholar 

  11. Imada M, Yagyuu T, Ueyama Y, Maeda M, Yamamoto K, Kurokawa S, Jo J, Tabata Y, Tanaka Y, Kirita T. Prevention of tooth extraction-triggered bisphosphonate-related osteonecrosis of the jaws with basic fibroblast growth factor: An experimental study in rats. PLoS ONE. 2019;14:e0211928.

    Article  Google Scholar 

  12. Adachi N, Ayukawa Y, Yasunami N, Furuhashi A, Imai M, Sanda K, Atsuta I, Koyano K. Preventive effect of fluvastatin on the development of medication-related osteonecrosis of the jaw. Sci Rep. 2020;10:5620.

    Article  Google Scholar 

  13. Kuroda Y, Kawai T, Goto K, Matsuda S. Clinical application of injectable growth factor for bone regeneration: a systematic review. Inflamm Regen. 2019;39:20.

    Article  Google Scholar 

  14. Alonso-Rodriguez E, González-Martín-Moro J, Cebrián-Carretero JL, Del Castillo JL, Pozo-Kreilinger JJ, Ruiz-Bravo E, García-Arranz M, Hernández-Godoy J, Burgueño M. Bisphosphonate-related osteonecrosis. Application of adipose-derived stem cells in an experimental murine model. Med Oral Patol Oral Cir Bucal. 2019;24:e529–36.

    PubMed  PubMed Central  Google Scholar 

  15. Kanematsu A, Marui A, Yamamoto S, Ozeki M, Hirano Y, Yamamoto M, Ogawa O, Komeda M, Tabata Y. Type I collagen can function as a reservoir of basic fibroblast growth factor. J Contorol Release. 2004;99:281–92.

    Article  Google Scholar 

  16. Abe Y, Iba K, Sasaki K, Chiba H, Kanaya K, Kawamata T, Oda K, Amizuka N, Sasaki M, Yamashita T. Inhibitory effect of bisphosphonate on osteoclast function contributes to improved skeletal pain in ovariectomized mice. J Bone Miner Metab. 2015;33:125–34.

    Article  Google Scholar 

  17. Pettway GJ, Meganck JA, Koh AJ, Keller ET, Goldstein SA, McCauley LK. Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation. Bone. 2008;42:806–18.

    Article  Google Scholar 

  18. Hata S. Effect of oral administration of simvastatin on bone regeneration process in ovariectomized rat. J Hard Tissue Biol. 2009;18:47–56.

    Article  Google Scholar 

  19. Vidal-Gutiérrez X, Gómez-Clavel JF, Gaitán-Cepeda LA. Dental extraction following zoledronate, induces osteonecrosis in rat’s jaw. Med Oral Patol Oral Cir Bucal. 2017;22:e177.

    PubMed  PubMed Central  Google Scholar 

  20. Williams DW, Lee C, Kim T, Yagita H, Wu H, Park S, Yang P, Liu H, Shi S, Shin KH, Kang MK, Park NH, Kim RH. Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κB ligand antibody in mice. Am J Pathol. 2014;184:30843093.

    Article  Google Scholar 

  21. Ando Y, Matsubara K, Ishikawa J, Fujio M, Shohara R, Hibi H, Ueda M, Yamamoto A. Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms. Bone. 2014;61:82–90.

    Article  Google Scholar 

  22. Kawai T, Katagiri W, Osugi M, Sugimura Y, Hibi H, Ueda M. Secretomes from bone marrow-derived mesenchymal stromal cells enhance periodontal tissue regeneration. Cytotherapy. 2015;17:369–81.

    Article  Google Scholar 

  23. Alge DL, Zhou D, Adams LL, Wyss BK, Shadday MD, Woods EJ, Gabriel Chu TM, Goebel WS. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Reg Med. 2010;4:73–81.

    Google Scholar 

  24. Abraham S, Rangaswamy SP, Chinnaiah A. Evaluation of recombinant human vascular endothelial growth factor VEGF121-loaded poly-l-lactide microparticles as a controlled release delivery system. Turk J Biol. 2020;44:34–47.

    PubMed  PubMed Central  Google Scholar 

  25. Tabata Y, Ikada Y. Vascularization effect of basic fibroblast growth factor released from gelatin hydrogels with different biodegradabilities. Biomaterials. 1999;20:2169–74.

    Article  Google Scholar 

  26. Gao SY, Lin RB, Huang SH, Liang YH, Li X, Zhang SE, Ouyang DQ, Li K, Zheng GS, Liao GQ. PDGF-BB exhibited therapeutic effects on rat model of bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis and osteogenesis. Bone. 2019;1:115117.

    Google Scholar 

  27. Basso FG, Turrioni APS, Hebling J, de Souza Costa CA. Effects of zoledronic acid on odontoblast-like cells. Arch Oral Biol. 2013;58:467–73.

    Article  Google Scholar 

  28. Cankaya M, Senel FC, Duman MK, Muci E, Dayisoylu EH, Balaban F. The effects of chronic zoledronate usage on the jaw and long bones evaluated using RANKL and osteoprotegerin levels in an animal model. Int J Oral Maxillofac Surg. 2013;42:1134–9.

    Article  Google Scholar 

  29. Basso FG, Turrioni AP, Hebling J, de Souza Costa CA. Zoledronic acid inhibits human osteoblast activities. Gerontology. 2013;59:534–41.

    Article  Google Scholar 

  30. Tamari T, Elimelech R, Cohen G, Cohen T, Doppelt O, Eskander-Hashoul L, Zigdon-Giladi H. Endothelial progenitor cells inhibit jaw osteonecrosis in a rat model: a major adverse effect of bisphosphonate therapy. Sci Rep. 2019;9:18896.

    Article  Google Scholar 

  31. Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J Clin Invest. 2016;126:509–26.

    Article  Google Scholar 

  32. Tarkka T, Sipola A, Jämsä T, Soini Y, Ylä-Herttuala S, Tuukkanen J, Hautala T. Adenoviral VEGF-A gene transfer induces angiogenesis and promotes bone formation in healing osseous tissues. J Gene Med. 2003;5:560–6.

    Article  Google Scholar 

  33. Hiraki T, Kunimatsu R, Nakajima K, Abe T, Yamada S, Rikitake K, Tanimoto K. Stem cell-derived conditioned media from human exfoliated deciduous teeth promote bone regeneration. Oral Dis. 2020;26:381–90.

    Article  Google Scholar 

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Authors and Affiliations

  1. Course of Clinical Science, Field of Oral and Maxillofacial Surgery and Systemic Medicine, Oral and Maxillofacial Surgery, Graduate School of Life Dentistry At Niigata, The Nippon Dental University, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan

    Hiroki Kushiro & Akira Tanaka

  2. Department of Oral and Maxillofacial Surgery, School of Life Dentistry At Niigata, The Nippon Dental University, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan

    Haruka Takahashi & Akira Tanaka

  3. Division of Cell Regeneration and Transplantation, Advanced Research Center School of Life Dentistry At Niigata, The Nippon Dental University, 1-8 Hamaura-cho, Chuo-ku, Niigata, 951-8580, Japan

    Haruka Takahashi & Akira Tanaka

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  1. Hiroki Kushiro
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  2. Haruka Takahashi
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  3. Akira Tanaka
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Correspondence to Hiroki Kushiro.

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The authors declare that they have no conflict of interest.

Ethical approval

Human DPSC was collected after the approval of the institutional review board of the School of Life Dentistry at Niigata, The Nippon Dental University (approval no. ECNG-H-121). Animal study was approved by the institutional review board of the School of Life Dentistry at Niigata, The Nippon Dental University (approval no. 196).

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Kushiro, H., Takahashi, H. & Tanaka, A. Effects of the prevention of medication-related osteonecrosis of the jaw by local administration of a dental pulp stem cell-conditioned medium to the rat tooth extraction socket. Odontology 109, 836–844 (2021). https://doi.org/10.1007/s10266-021-00607-2

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