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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References
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.
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.
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.
Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29:1727–45.
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.
He F, Antonucci L, Karin M. NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis. 2020;41:405–16.
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.
Sun YX, Xu AH, Yang Y, Li J. Role of Nrf2 in bone metabolism. J Biomed Sci. 2015;22:101.
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.
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.
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.
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.
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.
Tomlinson RE, Christiansen BA, Giannone AA, Genetos DC. The role of nerves in skeletal development, adaptation, and aging. Front Endocrinol (Lausanne). 2020;11:646.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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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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DOI: https://doi.org/10.1007/s10266-022-00773-x