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Journal of Bone and Mineral Metabolism
Published in: Journal of Bone and Mineral Metabolism 3/2021

01-05-2021 | Tooth Extraction | Original Article

Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw

Authors: Tomoya Soma, Ryotaro Iwasaki, Yuiko Sato, Tami Kobayashi, Satoshi Nakamura, Yosuke Kaneko, Eri Ito, Hiroyuki Okada, Hisato Watanabe, Kana Miyamoto, Morio Matsumoto, Masaya Nakamura, Seiji Asoda, Hiromasa Kawana, Taneaki Nakagawa, Takeshi Miyamoto

Published in: Journal of Bone and Mineral Metabolism | Issue 3/2021

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Abstract

Introduction

Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients’ activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear.

Materials and Methods

We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate.

Results

We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment.

Conclusions

Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.
Appendix
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Literature
1.
Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117PubMed
2.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update. J Oral Maxillofac Surg 72:1938–1956PubMed
3.
Miksad RA, Lai KC, Dodson TB, Woo SB, Treister NS, Akinyemi O, Bihrle M, Maytal G, August M, Gazelle GS, Swan JS (2011) Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw. Oncologist 16:121–132PubMedPubMedCentral
4.
Khamaisi M, Regev E, Yarom N, Avni B, Leitersdorf E, Raz I, Elad S (2007) Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 92:1172–1175PubMed
5.
Molcho S, Peer A, Berg T, Futerman B, Khamaisi M (2013) Diabetes microvascular disease and the risk for bisphosphonate-related osteonecrosis of the jaw: a single center study. J Clin Endocrinol Metab 98:E1807–1812PubMed
6.
Berti-Couto SA, Vasconcelos AC, Iglesias JE, Figueiredo MA, Salum FG, Cherubini K (2014) Diabetes mellitus and corticotherapy as risk factors for alendronate-related osteonecrosis of the jaws: a study in Wistar rats. Head Neck 36:84–93PubMed
7.
Kastritis E, Melea P, Bagratuni T, Melakopoulos I, Gavriatopoulou M, Roussou M, Migkou M, Eleutherakis-Papaiakovou E, Terpos E, Dimopoulos MA (2017) Genetic factors related with early onset of osteonecrosis of the jaw in patients with multiple myeloma under zoledronic acid therapy. Leuk Lymphoma 58:2304–2309PubMed
8.
Rachner TD, Platzbecker U, Felsenberg D, Hofbauer LC (2013) Osteonecrosis of the jaw after osteoporosis therapy with denosumab following long-term bisphosphonate therapy. Mayo Clin Proc 88:418–419PubMed
9.
Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836PubMed
10.
Otto S, Troltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C (2015) Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg 43:847–854PubMed
11.
Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E (2009) Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20:137–145PubMed
12.
Sakaguchi O, Kokuryo S, Tsurushima H, Tanaka J, Habu M, Uehara M, Nishihara T, Tominaga K (2015) Lipopolysaccharide aggravates bisphosphonate-induced osteonecrosis in rats. Int J Oral Maxillofac Surg 44:528–534PubMed
13.
Manzano-Moreno FJ, Ramos-Torrecillas J, De Luna-Bertos E, Ruiz C, Garcia-Martinez O (2015) High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J Craniomaxillofac Surg 43:396–401PubMed
14.
Marx RE (2014) A decade of bisphosphonate bone complications: what it has taught us about bone physiology. Int J Oral Maxillofac Implants 29:e247–258PubMed
15.
Fliefel R, Troltzsch M, Kuhnisch J, Ehrenfeld M, Otto S (2015) Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int J Oral Maxillofac Surg 44:568–585PubMed
16.
Kang B, Cheong S, Chaichanasakul T, Bezouglaia O, Atti E, Dry SM, Pirih FQ, Aghaloo TL, Tetradis S (2013) Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. J Bone Miner Res 28:1631–1640PubMedPubMedCentral
17.
Park S, Kanayama K, Kaur K, Tseng HC, Banankhah S, Quje DT, Sayre JW, Jewett A, Nishimura I (2015) Osteonecrosis of the jaw developed in mice: disease variants regulated by gammadelta t cells in oral mucosal barrier immunity. J Biol Chem 290:17349–17366PubMedPubMedCentral
18.
Soundia A, Hadaya D, Esfandi N, de Molon RS, Bezouglaia O, Dry SM, Pirih FQ, Aghaloo T, Tetradis S (2016) Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone 90:133–141PubMedPubMedCentral
19.
Sun Y, Kaur K, Kanayama K, Morinaga K, Park S, Hokugo A, Kozlowska A, McBride WH, Li J, Jewett A, Nishimura I (2016) Plasticity of Myeloid Cells during Oral Barrier Wound Healing and the Development of Bisphosphonate-related Osteonecrosis of the Jaw. J Biol Chem 291:20602–20616PubMedPubMedCentral
20.
Kuroshima S, Sasaki M, Nakajima K, Tamaki S, Hayano H, Sawase T (2018) Transplantation of noncultured stromal vascular fraction cells of adipose tissue ameliorates osteonecrosis of the jaw-like lesions in mice. J Bone Miner Res 33:154–166PubMed
21.
Bi Y, Gao Y, Ehirchiou D, Cao C, Kikuiri T, Le A, Shi S, Zhang L (2010) Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol 177:280–290PubMedPubMedCentral
22.
Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, Chen C, Chen W, Wang S, Le AD, Shi S (2010) Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res 25:1668–1679PubMedPubMedCentral
23.
Zhao Y, Wang L, Liu Y, Akiyama K, Chen C, Atsuta I, Zhou T, Duan X, Jin Y, Shi S (2012) Technetium-99 conjugated with methylene diphosphonate ameliorates ovariectomy-induced osteoporotic phenotype without causing osteonecrosis in the jaw. Calcif Tissue Int 91:400–408PubMed
24.
Zandi M, Dehghan A, Malekzadeh H, Janbaz P, Ghadermazi K, Amini P (2016) Introducing a protocol to create bisphosphonate-related osteonecrosis of the jaw in rat animal model. J Craniomaxillofac Surg 44:271–278PubMed
25.
Allen MR (2015) Medication-related osteonecrosis of the jaw: basic and translational science updates. Oral Maxillofac Surg Clin North Am 27:497–508PubMed
26.
Aghaloo TL, Cheong S, Bezouglaia O, Kostenuik P, Atti E, Dry SM, Pirih FQ, Tetradis S (2014) RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease. J Bone Miner Res 29:843–854PubMedPubMedCentral
27.
Conte Neto N, Spolidorio LC, Andrade CR, Bastos S, Guimaraes M, Marcantonio E Jr (2013) Experimental development of bisphosphonate-related osteonecrosis of the jaws in rodents. Int J Exp Pathol 94:65–73PubMedPubMedCentral
28.
Otto S, Pautke C, Martin Jurado O, Nehrbass D, Stoddart MJ, Ehrenfeld M, Zeiter S (2017) Further development of the MRONJ minipig large animal model. J Craniomaxillofac Surg 45:1503–1514PubMed
29.
Morita M, Iwasaki R, Sato Y, Kobayashi T, Watanabe R, Oike T, Nakamura S, Keneko Y, Miyamoto K, Ishihara K, Iwakura Y, Ishii K, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T (2017) Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis. Sci Rep 7:46322PubMedPubMedCentral
30.
Oike T, Kanagawa H, Sato Y, Kobayashi T, Nakatsukasa H, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Yoshimura A, Iwakura Y, Takeuchi T, Matsumoto M, Nakamura M, Niki Y, Miyamoto T (2018) IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse. Sci Rep 8:15783PubMedPubMedCentral
31.
Mori T, Sato Y, Miyamoto K, Kobayashi T, Shimizu T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Iwasaki R, Kawana H, Morioka H, Matsumoto M, Saya H, Toyama Y, Miyamoto T (2014) TNFalpha promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. Oncogene 33:4236–4241PubMed
32.
Brunner JS, Vulliard L, Hofmann M, Kieler M, Lercher A et al (2020) Environmental arginine controls multinuclear giant cell metabolism and formation. Nat Commun 11:431PubMedPubMedCentral
33.
Gurt I, Artsi H, Cohen-Kfir E, Hamdani G, Ben-Shalom G, Feinstein B, El-Haj M, Dresner-Pollak R (2015) The Sirt1 activators SRT2183 and SRT3025 inhibit RANKL-induced osteoclastogenesis in bone marrow-derived macrophages and down-regulate Sirt3 in Sirt1 null cells. PLoS ONE 10:e0134391PubMedPubMedCentral
34.
Sato Y, Miyauchi Y, Yoshida S, Morita M, Kobayashi T, Kanagawa H, Katsuyama E, Fujie A, Hao W, Tando T, Watanabe R, Miyamoto K, Morioka H, Matsumoto M, Toyama Y, Miyamoto T (2014) The vitamin D analogue ED71 but Not 1,25(OH)2D3 targets HIF1α protein in osteoclasts. PLoS ONE 9:e111845–e111845PubMedPubMedCentral
35.
Katsuyama E, Miyamoto H, Kobayashi T, Sato Y, Hao W, Kanagawa H, Fujie A, Tando T, Watanabe R, Morita M, Miyamoto K, Niki Y, Morioka H, Matsumoto M, Toyama Y, Miyamoto T (2015) Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. J Biol Chem 290:716–726PubMed
36.
Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879–882PubMed
37.
Rosen LS, Gordon DH, Dugan W Jr, Major P, Eisenberg PD, Provencher L, Kaminski M, Simeone J, Seaman J, Chen BL, Coleman RE (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36–43PubMed
38.
Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092PubMed
39.
Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carriere P, Dansey R (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23:1341–1347PubMed
40.
Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK et al (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30:3–23PubMed
41.
Allen MR (2009) Bisphosphonates and osteonecrosis of the jaw: moving from the bedside to the bench. Cells Tissues Organs 189:289–294PubMed
42.
Cheung A, Seeman E (2010) Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. N Engl J Med 363:2473–2474PubMed
43.
Kwon YD, Lee DW, Choi BJ, Lee JW, Kim DY (2012) Short-term teriparatide therapy as an adjunctive modality for bisphosphonate-related osteonecrosis of the jaws. Osteoporos Int 23:2721–2725PubMed
44.
Harper RP, Fung E (2007) Resolution of bisphosphonate-associated osteonecrosis of the mandible: possible application for intermittent low-dose parathyroid hormone [rhPTH(1-34)]. J Oral Maxillofac Surg 65:573–580PubMed
45.
Miyamoto T, Ohneda O, Arai F, Iwamoto K, Okada S, Takagi K, Anderson DM, Suda T (2001) Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 98:2544–2554PubMed
46.
Kassem A, Henning P, Lundberg P, Souza PP, Lindholm C, Lerner UH (2015) Porphyromonas gingivalis stimulates bone resorption by enhancing RANKL (receptor activator of NF-κB ligand) through activation of toll-like receptor 2 in osteoblasts. J Biol Chem 290:20147–20158PubMedPubMedCentral
47.
Kanagawa H, Niki Y, Kobayashi T, Sato Y, Katsuyama E, Fujie A, Hao W, Miyamoto K, Tando T, Watanabe R, Morita M, Morioka H, Matsumoto M, Toyama Y, Miyamoto T (2015) Mycobacterium tuberculosis promotes arthritis development through Toll-like receptor 2. J Bone Miner Metab 33:135–141PubMed
48.
Miyamoto K, Yoshida S, Kawasumi M, Hashimoto K, Kimura T et al (2011) Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J Exp Med 208:2175–2181PubMedPubMedCentral
49.
Kotian P, Boloor A, Sreenivasan S (2016) Study of adverse effect profile of parenteral zoledronic acid in female patients with osteoporosis. J Clin Diagn Res 10:04–06
50.
Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 139:101–111PubMedPubMedCentral
51.
Park W, Kim NK, Kim MY, Rhee YM, Kim HJ (2010) Osteonecrosis of the jaw induced by oral administration of bisphosphonates in Asian population: five cases. Osteoporos Int 21:527–533PubMed
52.
Malden N, Beltes C, Lopes V (2009) Dental extractions and bisphosphonates: the assessment, consent and management, a proposed algorithm. Br Dent J 206:93–98PubMed
53.
Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N (2010) Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060–1064PubMed
Metadata
Title
Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw
Authors
Tomoya Soma
Ryotaro Iwasaki
Yuiko Sato
Tami Kobayashi
Satoshi Nakamura
Yosuke Kaneko
Eri Ito
Hiroyuki Okada
Hisato Watanabe
Kana Miyamoto
Morio Matsumoto
Masaya Nakamura
Seiji Asoda
Hiromasa Kawana
Taneaki Nakagawa
Takeshi Miyamoto
Publication date
01-05-2021
Publisher
Springer Singapore
Published in
Journal of Bone and Mineral Metabolism / Issue 3/2021
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-020-01174-2

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