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BMC Oral Health

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Open Access 01-12-2022 | Research

Role of PI3K in the bone resorption of apical periodontitis

Authors: LiNa Wang, Ming Dong, DongMei Shi, CaiHui Yang, Shuo Liu, Lu Gao, WeiDong Niu

Published in: BMC Oral Health | Issue 1/2022

Abstract

Background

Phosphoinositide 3-kinase (PI3K) is located within cells, and is involved in regulating cell survival, proliferation, apoptosis and angiogenesis. The purpose of this study was to investigate the role of PI3K in the process of bone destruction in apical periodontitis, and provide reference data for the treatment of this disease.

Methods

The relative mRNA expression of PI3K, Acp5 and NFATc1 in the normal human periodontal ligament and in chronic apical periodontitis were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). A mouse model of apical periodontitis was established by root canal exposure to the oral cavity, and HE staining was used to observe the progress of apical periodontitis. Immunohistochemical staining was used to detect the expression of PI3K and AKT in different stages of apical periodontitis, while enzymatic histochemical staining was used for detection of osteoclasts. An Escherichia coli lipopolysaccharide (LPS)-mediated inflammatory environment was also established at the osteoclast and osteoblast level, and osteoclasts or osteoblasts were treated with the PI3K inhibitor LY294002 to examine the role of PI3K in bone resorption.

Results

The expression of PI3K, Acp5 and NFATc1 genes in chronic apical periodontitis sample groups was significantly increased relative to healthy periodontal ligament tissue (P < 0.05). Mouse apical periodontitis was successfully established and bone resorption peaked between 2 and 3 weeks (P < 0.05). The expression of PI3K and Akt increased with the progression of inflammation, and reached a peak at 14 days (P < 0.05). The gene and protein expression of PI3K, TRAP and NFATc1 in osteoclasts were significantly increased (P < 0.05) in the E. coli LPS-mediated inflammatory microenvironment compared to the normal control group. Meanwhile in osteoblasts, the gene and protein expression of PI3K, BMP-2 and Runx2 were significantly reduced (P < 0.05) in the inflammatory microenvironment. With the addition of LY294002, expressions of bone resorption-related factors (TRAP, NFATc1) and bone formation-related factors (BMP-2, Runx2) significantly decreased (P < 0.05).

Conclusions

Under the inflammatory environment induced by LPS, PI3K participates in the occurrence and development of chronic apical periodontitis by regulating the proliferation and differentiation of osteoclasts and osteoblasts.

Croitoru IC, CrăiŢoiu Ş, Petcu CM, Mihăilescu OA, Pascu RM, Bobic AG, et al. Clinical, imagistic and histopathological study of chronic apical periodontitis. Rom J Morphol Embryol. 2016;57:719–28.PubMed

Jakovljevic A, Miletic M, Nikolic N, Beljic-Ivanovic K, Andric M, Milasin J. Notch signaling pathway mediates alveolar bone resorption in apical periodontitis. Med Hypotheses. 2019;124:87–90.PubMedCrossRef

Krakauer T. Inflammasomes, autophagy, and cell death: the trinity of innate host defense against intracellular bacteria. Mediat Inflamm. 2019;2019:2471215.CrossRef

Braz-Silva PH, Bergamini ML, Mardegan AP, De Rosa CS, Hasseus B, Jonasson P. Inflammatory profile of chronic apical periodontitis: a literature review. Acta Odontol Scand. 2019;77:173–80.PubMedCrossRef

Loureiro C, Buzalaf MAR, Moraes FRN, Ventura TMO, Pelá VT, Pessan JP, et al. Quantitative proteomic analysis in symptomatic and asymptomatic apical periodontitis. Int Endod J. 2021;54:834–47.PubMedCrossRef

Jakovljevic A, Nikolic N, Carkic J, Andric M, Miletic M, Beljic-Ivanovic K, et al. Notch—a possible mediator between Epstein–Barr virus infection and bone resorption in apical periodontitis. Acta Odontol Scand. 2020;78:126–31.PubMedCrossRef

Paula-Silva FWG, Ribeiro-Santos FR, Petean IBF, Manfrin Arnez MF, Almeida-Junior LA, Carvalho FK, et al. Root canal contamination or exposure to lipopolysaccharide differentially modulate prostaglandin E2 and leukotriene B4 signaling in apical periodontitis. J Appl Oral Sci. 2020;28:e20190699.PubMedPubMedCentralCrossRef

Assed S, Ito IY, Leonardo MR, Silva LAB, Lopatin DE. Anaerobic microorganisms in root canals of human teeh with chronic apical periodontitis detected by indirect immunofluorescence. Endod Dent Traumatol. 1996;12:66–9.PubMedCrossRef

Nelson-Filho P, Leonardo MR, Silva LA, Assed S. Radiographic evaluation of the effect of endotoxin (LPS) plus calcium hydroxide on apical and periapical tissues of dogs. J Endod. 2002;28:694–6.PubMedCrossRef

10.

Hong CY, Lin SK, Kok SH, Cheng SJ, Lee MS, Wang TM, et al. The role of lipopolysaccharide in infectious bone resorption of periapical lesion. J Oral Pathol Med. 2004;33:162–9.PubMedCrossRef

11.

Silva LA, Silva RA, Branco LG, Navarro VP, Nelson-Filho P. Quantitative radiographic evaluation of periapical bone resorption in dog’s teeth contaminated with bacterial endotoxin (LPS) associated or not with calcium hydroxide. Braz Dent J. 2008;19:296–300.PubMedCrossRef

12.

Gomes BPFA, Herrera DR. Etiologic role of root canal infection in apical periodontitis and its relationship with clinical symptomatology. Braz Oral Res. 2018;32(suppl 1):e69.PubMedCrossRef

13.

Beaty CD, Franklin TL, Uehara Y, Wilson CB. Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction. Eur J Immunol. 1994;24:1278–84.PubMedCrossRef

14.

Wang L, Jin H, Ao X, Dong M, Liu S, Lu Y, et al. JAK2-STAT3 signaling pathway is involved in rat periapical lesions induced by Enterococcus faecalis. Oral Dis. 2019;25:1769–79.PubMedCrossRef

15.

Yin W, Dong M, Ye D, Liu Q, Liu S, Shi C, et al. Cathepsin C promotes the progression of periapical periodontitis. Sci Bull. 2020;65:951–7.CrossRef

16.

Wang L, Jin H, Ye D, Wang J, Ao X, Dong M, et al. Enterococcus faecalis lipoteichoic acid-induced NLRP3 inflammasome via the activation of NF-κB pathway. J Endod. 2016;42:1093–100.PubMedCrossRef

17.

Leonardo MR, Silva RA, Assed S, Nelson-Filho P. Importance of bacterial endotoxin (LPS) in endodontics. J Appl Oral Sci. 2004;12:93–8.PubMedCrossRef

18.

Kang H, Chang W, Hurley M, Vignery A, Wu D. Important roles of PI3Kγ in osteoclastogenesis and bone homeostasis. PNAS J. 2010;107:12901–6.CrossRef

19.

Wu CM, Chen PC, Li TM, Fong YC, Tang CH. Si-Wu-tang extract stimulates bone formation through PI3K/Akt/NF-κB signaling pathways in osteoblasts. BMC Complement Altern Med. 2013;13:277.PubMedPubMedCentralCrossRef

20.

Moon JB, Kim JH, Kim K, Youn BU, Lee Y, Kin N. Akt induces osteoclast differentiation through regulating the GSK3β /NFATc1 signaling cascade. J Immunol. 2012;188:163–9.PubMedCrossRef

21.

Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, et al. Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE. 2007;2:e1058.PubMedPubMedCentralCrossRef

22.

Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG. Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and smad-dependent BMP-2gene transcription. J Biol Chem. 2002;277:33361–8.PubMedCrossRef

23.

Viñals F, López-Rovira T, Rosa JL, Ventura F. Inhibition of PI3K/ p70S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2. FEBS Lett. 2002;5:99–104.CrossRef

24.

Lin C, Shao Y, Zeng C, Zhao C, Fang H, Wang L, et al. Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis. J Cell Physiol. 2018;233(8):6135–47.PubMedCrossRef

25.

Orstavik D, Kerekes K, Eriksen HM. The periapical index: a scoring system for radiographic assessment of apical periodontitis. Endod Dent Traumatol. 1986;2(1):20–34.PubMedCrossRef

26.

Boubaris M, Chan KL, Zhao W, Cameron A, Sun J, Love R, et al. A novel volume-based cone-beam computed tomographic periapical index. J Endod. 2021;47(8):1308–13.PubMedCrossRef

27.

Dal-Fabbro R, Cosme-Silva L, Rezende Silva Martins de Oliveira F, Capalbo LC, Plazza FA, Ervolino E, et al. Effect of red wine or its polyphenols on induced apical periodontitis in rats. Int Endod J. 2021;54(12):2276–89.PubMedCrossRef

28.

Brey EM, Lalani Z, Johnston C, Wong M, McIntire LV, Duke PJ, et al. Automated selection of DAB-labeled tissue for immunohistochemical quantification. J Histochem Cytochem. 2003;51(5):575–84.PubMedCrossRef

29.

Maximova OA, Taffs RE, Pomeroy KL, Piccardo P, Asher DM. Computerized morphometric analysis of pathological prion protein deposition in scrapie-infected hamster brain. J Histochem Cytochem. 2006;54(1):97–107.PubMedCrossRef

30.

Valerio MS, Basilakos DS, Kirkpatrick JE, Chavez M, Hathaway-Schrader J, Herbert BA, et al. Sex-based differential regulation of bacterial-induced bone resorption. J Periodontal Res. 2017;52(3):377–87.PubMedCrossRef

31.

Rossi A, Rocha LB, Rossi MA. Interferon-gamma, interleukin-10, Intercellular adhesion molecule-1, and chemokine receptor 5, but not interleukin-4, attenuate the development of periapical lesions. J Endod. 2008;34(1):31–8.PubMedCrossRef

32.

Wu Y, Sun H, Yang B, Liu X, Wang J. 5-lipoxygenase knockout aggravated apical periodontitis in a murine model. J Dent Res. 2018;97:442–50.PubMedCrossRef

33.

Paula-Silva FWG, Ribeiro-Santos FR, Petean IBF, Manfrin Arnez MF, Almeida-Junior LA, Carvalho FK, et al. Root canal contamination or exposure to lipopolysaccharide differentially modulate prostaglandin E 2 and leukotriene B 4 signaling in apical periodontitis. J Appl Oral Sci. 2020;28:e20190699.PubMedPubMedCentralCrossRef

34.

Silva LA, Nelson-Filho P, Leonardo MR, Rossi MA, Pansani CA. Effect of calcium hydroxide on bacterial endotoxin in vivo. J Endod. 2002;28:94–8.PubMedCrossRef

35.

Paula-Silva FW, Petean IB, Silva LA, Faccioli LH. Dual role of 5-lipoxygenase in osteoclastogenesis in bacterial-induced apical periodontitis. J Endod. 2016;42:447–54.PubMedCrossRef

36.

Silva RAB, Sousa-Pereira AP, Lucisano MP, Romualdo PC, Paula-Silva FWG, Consolaro A, et al. Alendronate inhibits osteocyte apoptosis and inflammation via IL-6, inhibiting bone resorption in periapical lesions of ovariectomized rats. Int Endod J. 2020;53(1):84–96.PubMedCrossRef

37.

Xi JC, Zang HY, Guo LX, Xue HB, Liu XD, Bai YB, et al. The PI3K/AKT cell signaling pathway is involved in regulation of osteoporosis. J Recept Signal Transduct Res. 2015;35:640–5.PubMedCrossRef

38.

Lin C, Shao Y, Zeng C, Zhao C, Fang H, Wang L, et al. Blocking PI3K/AKT signaling inhibitsbone sclerosis in subchondral bone and attenuates post-traumatic osteoarthritis. J Cell Physiol. 2018;233:6135–47.PubMedCrossRef

39.

Huang S, Jin A. ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways. J Cell Biochem. 2018;119:2248–57.PubMedCrossRef

40.

Wang X, DingJ MLH. PI3K isoform-selective inhibitors: next-generation targeted cancer therapies. Acta Pharmacol Sin. 2015;36:1170–6.PubMedPubMedCentralCrossRef

41.

Wang S, Niu X, Bao X, Wang Q, Zhang J, Lu S, et al. The PI3K inhibitor buparlisib suppresses osteoclast formation and tumour cell growth in bone metastasis of lung cancer, as evidenced by multimodality molecular imaging. Oncol Rep. 2019;41:2636–46.PubMedPubMedCentral

42.

Lee SE, Woo KM, Kim SY, Kim HM, Kwack K, Lee ZH, et al. Thephospha-tidylinositol3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone. 2002;30:71–7.PubMedCrossRef

43.

Fujita T, Azuma Y, Komori T, Hattori Y, Yoshida C, Koida M, et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J Cell Physiol. 2018;233:6135–47.CrossRef

Title: Role of PI3K in the bone resorption of apical periodontitis
Authors: LiNa Wang
Ming Dong
DongMei Shi
CaiHui Yang
Shuo Liu
Lu Gao
WeiDong Niu
Publication date: 01-12-2022
Publisher: BioMed Central
Published in: BMC Oral Health / Issue 1/2022
Electronic ISSN: 1472-6831
DOI: https://doi.org/10.1186/s12903-022-02364-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of PI3K in the bone resorption of apical periodontitis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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