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Denervation delays initial bone healing of rat tooth extraction socket

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Abstract

Functions of nerves on bone has been a subject of intense research. The aim of this study is to observe initial bone healing of rat tooth extraction socket after inferior alveolar nerve transection. The bilateral mandible second molars of eighteen Wistar rats were extracted in the study. The rats also suffered from right inferior alveolar nerve transection simultaneously (D + E group), only extraction as control (E group). One, two and four weeks after extraction, the mandibles were taken out for histological observation, TRAP staining, immunofluorescence, immunohistochemistry and micro-computed tomography (Micro-CT). Mouse bone marrow derived macrophages (BMMs) were cultured in vitro. Expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) were detected in vivo and vitro. The alveolar sockets had been filled to a large extent with new bone at 4 weeks, but BV/TV and BMD decreased in the D + E group. Accordingly, Expressions of osteocalcin (OCN) and osteopontin (OPN) were down-regulated in the D + E group. Denervation increased TRAP-positive osteoclasts and decreased expressions of Nrf2 at 2 weeks after extraction. Decreased Nrf2 promoted osteoclast differentiation of BMMs in vitro. Denervation delays initial bone healing of rat tooth extraction socket. Osteoclast activation induced by decreased Nrf2 might participated in the process.

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Data availability

All data included in this study are available upon request by contact with the corresponding author.

References

  1. Wan QQ, Qin WP, Ma YX, Shen MJ, Li J, Zhang ZB, Chen JH, Tay FR, Niu LN. Crosstalk between bone and nerves within bone. Adv Sci. 2021;8:2003390.

    Article  Google Scholar 

  2. Yu X, Lv L, Zhang J, Zhang T, Xiao C, Li S. Expression of neuropeptides and bone remodeling-related factors during periodontal tissue regeneration in denervated rats. J Mol Histol. 2015;46:195–203.

    Article  PubMed  Google Scholar 

  3. Yu X, Gong Z, Lin Q, Wang W, Liu S, Li S. Denervation effectively aggravates rat experimental periodontitis. J Periodontal Res. 2017;52:1011–20.

    Article  PubMed  Google Scholar 

  4. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29:1727–45.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res. 2018;1865:721–33.

    Article  PubMed  Google Scholar 

  6. He F, Antonucci L, Karin M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis. 2020;41:405–16.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Xiong W, MacColl Garfinkel AE, Li Y, Benowitz LI, Cepko CL. NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage. J Clin Invest. 2015;125:1433–45.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sun YX, Xu AH, Yang Y, Li J. Role of Nrf2 in bone metabolism. J Biomed Sci. 2015;22:101.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sánchez-de-Diego C, Pedrazza L, Pimenta-Lopes C, Martinez-Martinez A, Dahdah N, Valer JA, Garcia-Roves P, Rosa JL, Ventura F. NRF2 function in osteocytes is required for bone homeostasis and drives osteocytic gene expression. Redox Biol. 2021;40: 101845.

    Article  PubMed  Google Scholar 

  10. Kitaoka Y, Takeda K, Tamura Y, Fujimaki S, Takemasa T, Hatta H. Nrf2 deficiency does not affect denervation-induced alterations in mitochondrial fission and fusion proteins in skeletal muscle. Physiol Rep. 2016;4: e13064.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Li J, Sheng Z, Sun J, Wang R, Yu X. Characterizations of alveolar repair after mandibular second molar extraction: an experimental study in rats. J Appl Oral Sci. 2022;30: e20220010.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yu X, Zheng F, Shang W, Du Y, Zhen J, Mao Y, Zhang S. Isorhamnetin 3-O-neohesperidoside promotes the resorption of crown-covered bone during tooth eruption by osteoclastogenesis. Sci Rep. 2020;10:5172.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Xu Y, Xia M, Chen T, Yang Y, Fu G, Ji P, Wu Q. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann N Y Acad Sci. 2019;1448:52–64.

    Article  PubMed  Google Scholar 

  14. Tomlinson RE, Christiansen BA, Giannone AA, Genetos DC. The role of nerves in skeletal development, adaptation, and aging. Front Endocrinol (Lausanne). 2020;11:646.

    Article  PubMed  Google Scholar 

  15. Chen H, Hu B, Lv X, Zhu S, Zhen G, Wan M, Jain A, Gao B, Chai Y, Yang M, Wang X. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat Commun. 2019;10:181.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yamashiro T, Fujiyama K, Fujiyoshi Y, Inaguma N, Takano-Yamamoto T. Inferior alveolar nerve transection inhibits increase in osteoclast appearance during experimental tooth movement. Bone. 2000;26:663–9.

    Article  PubMed  Google Scholar 

  17. Wu Q, Yang B, Cao C, Guang M, Gong P. Age-dependent impact of inferior alveolar nerve transection on mandibular bone metabolism and the underlying mechanisms. J Mol Histol. 2016;47:579–86.

    Article  PubMed  Google Scholar 

  18. Xie D, Xu Y, Yang Y, Hua Z, Li J, Fu G, Wu Q. Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene-related peptide and substance P. Ann N Y Acad Sci. 2021;1487:56–73.

    Article  PubMed  Google Scholar 

  19. Iizuka T, Miller SC, Marks SC Jr. Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats. J Oral Pathol Med. 1992;21:150–5.

    Article  PubMed  Google Scholar 

  20. Yamashita J, Sawa N, Sawa Y, Miyazono S. Effect of bisphosphonates on healing of tooth extraction wounds in infectious osteomyelitis of the jaw. Bone. 2021;143: 115611.

    Article  PubMed  Google Scholar 

  21. Cao J, Zhang S, Gupta A, Du Z, Lei D, Wang L, Wang X. Sensory nerves affect bone regeneration in rabbit mandibular distraction osteogenesis. Int J Med Sci. 2019;16:831–7.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sadr K, Aghbali A, Sadr M, Abachizadeh H, Azizi M, Mesgari AM. Effect of beta-blockers on number of osteoblasts and osteoclasts in alveolar socket following tooth extraction in wistar rats. J Dent (Shiraz). 2017;18:37–42.

    PubMed  Google Scholar 

  23. Han J, Yang K, An J, Jiang N, Fu S, Tang X. The role of NRF2 in bone metabolism - friend or foe? Front Endocrinol (Lausanne). 2022;13: 813057.

    Article  PubMed  Google Scholar 

  24. Sun YX, Li L, Corry KA, Zhang P, Yang Y, Himes E, Mihuti CL, Nelson C, Dai G, Li J. Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation. Bone. 2015;74:1–9.

    Article  PubMed  Google Scholar 

  25. Sun X, Xie Z, Hu B, Zhang B, Ma Y, Pan X, Huang H, Wang J, Zhao X, Jie Z, Shi P, Chen Z. The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling. Redox Biol. 2020;28: 101309.

    Article  PubMed  Google Scholar 

  26. Dang R, Wang M, Li X, Wang H, Liu L, Wu Q, Zhao J, Ji P, Zhong L, Licinio J, Xie P. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway. J Neuroinflammation. 2022;19:41.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yuan Y, Zhai Y, Chen J, Xu X, Wang H. Kaempferol ameliorates oxygen-glucose deprivation/reoxygenation-induced neuronal ferroptosis by activating Nrf2/SLC7A11/GPX4 Axis. Biomolecules. 2021;11:923.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lv Z, Wang F, Zhang X, Zhang X, Zhang J, Liu R. Etomidate attenuates the ferroptosis in myocardial ischemia/reperfusion rat model via Nrf2/HO-1 pathway. Shock. 2021;56:440–9.

    PubMed  Google Scholar 

  29. Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, Kariya Y, Kato G, Tabata Y, Penninger JM, Udagawa N, Aoki K, Suzuki H. Coupling of bone resorption and formation by RANKL reverse signalling. Nature. 2018;561(7722):195–200.

    Article  PubMed  Google Scholar 

  30. Narimiya T, Kanzaki H, Yamaguchi Y, Wada S, Katsumata Y, Tanaka K, Tomonari H. Nrf2 activation in osteoblasts suppresses osteoclastogenesis via inhibiting IL-6 expression. Bone Rep. 2019;1(11): 100228.

    Article  Google Scholar 

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Acknowledgements

Natural Science Foundation of Shandong Province (ZR2020MH182, ZR2021MH230), Clinical medicine science and technology innovation plan of Jinan (202019068, 2022-1-35) and the Dean's Research Fund of Jinan Stomatological Hospital (202102).

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Correspondence to Yi Du, Xiaohua Liu or Xijiao Yu.

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Sheng, Z., Zheng, F., Li, J. et al. Denervation delays initial bone healing of rat tooth extraction socket. Odontology 111, 640–648 (2023). https://doi.org/10.1007/s10266-022-00773-x

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