Skip to main content

Advertisement

SpringerLink
Log in

In vivo and In vitro Identification of Endocannabinoid Signaling in Periodontal Tissues and Their Potential Role in Local Pathophysiology

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The endocannabinoid system (ECS) with its binding receptors CB1 and CB2 impacts multiple pathophysiologies not only limited to neuronal psychoactivity. CB1 is assigned to cerebral neuron action, whereas CB2 is mainly expressed in different non-neuronal tissues and associated with immunosuppressive effects. Based on these tissue-selective CB receptor roles, it was the aim of this study to analyze potential expression in periodontal tissues under physiological conditions and inflammatory states. In vivo, CB receptor expression was investigated on human periodontal biopsies with or without bacterial inflammation and on rat maxillae with or without sterile inflammation. In vitro analyses were performed on human periodontal ligament (PDL) cells at rest or under mechanical strain via qRT-PCR, Western blot, and immunocytochemistry. P < 0.05 was set statistical significant. In vivo, CB1 expression was significantly higher in healthy PDL structures compared to CB2 (13.5% ± 1.3 of PDL tissues positively stained; 7.1% ± 0.9). Bacterial inflammation effected decrease in CB1 (9.7% ± 2.4), but increase in CB2 (14.7% ± 2.5). In contrast, sterile inflammation caused extensive CB1 (40% ± 1.9) and CB2 (41.7% ± 2.2) accumulations evenly distributed in the tooth surrounding PDL. In vitro, CB2 was ubiquitously expressed on gene and protein level. CB1 was constitutively expressed on transcriptional level (0.41% ± 0.09), even higher than CB2 (0.29% ± 0.06), but undetectable on protein level. Analyses further revealed expression changes of both receptors in mechanically loaded PDL cells. CB1 and CB2 are varyingly expressed in periodontal tissues, both adjusted by different entities of periodontal inflammation and by mechanical stress. This indicates potential ECS function as regulatory tool in controlling of periodontal pathophysiology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar YS (2015) Association between periodontitis and Alzheimer’s disease. N Am J Med Sci 7:241–246

    Article  PubMed  PubMed Central  Google Scholar 

  • American Academy of Periodontology (2015) American Academy of Periodontology Task Force report on the update to the 1999 classification of periodontal diseases and conditions. J Periodontol 86:835–838

    Article  Google Scholar 

  • Deschner J, Rath-Deschner B, Reimann S, Bourauel C, Götz W, Jepsen S, Jäger A (2007) Regulatory effects of biophysical strain on rat TMJ discs. Ann Anat 189:326–328

    Article  PubMed  Google Scholar 

  • Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784

    Article  PubMed  Google Scholar 

  • Elefteriou F (2008) Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys 473:231–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61

    Article  PubMed  Google Scholar 

  • Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    Article  CAS  PubMed  Google Scholar 

  • Hall M, Masella R, Meister M (2001) PDL neuron-associated neurotransmitters in orthodontic tooth movement: identification and proposed mechanism of action. Todays FDA 13:24–25

    CAS  PubMed  Google Scholar 

  • Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    Article  CAS  PubMed  Google Scholar 

  • Idris AI, van ‘t Hof RJ, Greig IR, Ridge SA, Baker D, Ross RA, Ralston SH (2005) Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 11:774–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ihenetu K, Molleman A, Parsons M, Whelan C (2003) Pharmacological characterisation of cannabinoid receptors inhibiting interleukin 2 release from human peripheral blood mononuclear cells. Eur J Pharmacol 464:207–215

    Article  CAS  PubMed  Google Scholar 

  • Jäger A, Kunert D, Friesen T, Zhang D, Lossdörfer S, Götz W (2008) Cellular and extracellular factors in early root resorption repair in the rat. Eur J Orthod 30:336–345

    Article  PubMed  Google Scholar 

  • Konermann A, Götz W, Wohlleber D, Knolle P, Deschner J, Jäger A (2012a) Osteoimmunological mechanisms involved in orthodontically and bacterially induced periodontal stress. J Orofac Orthop 73:430–439

    Article  CAS  PubMed  Google Scholar 

  • Konermann A, Stabenow D, Knolle PA, Held SA, Deschner J, Jäger A (2012b) Regulatory role of periodontal ligament fibroblasts for innate immune cell function and differentiation. Innate Immun 18:745–752

    Article  PubMed  Google Scholar 

  • Konermann A, Kantarci A, Wilbert S, Van Dyke T, Jäger A (2016a) Verification of γ-amino-butyric acid (GABA) signaling system components in periodontal ligament cells in vivo and in vitro. Cell Mol Neurobiol 36:1353–1363

    Article  CAS  PubMed  Google Scholar 

  • Konermann A, Van Dyke T, Kantarci A, Jäger A (2016b) GABAB receptors as modulating target for inflammatory responses of the periodontal ligament. Cell Mol Neurobiol. doi:10.1007/s10571-016-0439-z

    Google Scholar 

  • Kook SH, Jang YS, Lee JC (2011) Human periodontal ligament fibroblasts stimulate osteoclastogenesis in response to compression force through TNF-α-mediated activation of CD4+ T cells. J Cell Biochem 112:2891–2901

    Article  CAS  PubMed  Google Scholar 

  • Kozono S, Matsuyama T, Biwasa KK, Kawahara K, Nakajima Y, Yoshimoto T, Yonamine Y, Kadomatsu H, Tancharoen S, Hashiguchi T, Noguchi K, Maruyama I (2010) Involvement of the endocannabinoid system in periodontal healing. Biochem Biophys Res Commun 394:928–933

    Article  CAS  PubMed  Google Scholar 

  • Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36:277–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564

    Article  CAS  PubMed  Google Scholar 

  • Moazzam AA, Rajagopal SM, Sedghizadeh PP, Zada G, Habibian M (2015) Intracranial bacterial infections of oral origin. J Clin Neurosci 22:800–806

    Article  PubMed  Google Scholar 

  • Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65

    Article  CAS  PubMed  Google Scholar 

  • Nakajima Y, Furuichi Y, Biswas KK, Hashiguchi T, Kawahara K, Yamaji K, Uchimura T, Izumi Y, Maruyama I (2006) Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett 580:613–619

    Article  CAS  PubMed  Google Scholar 

  • Napimoga MH, Benatti BB, Lima FO, Alves PM, Campos AC, Pena-Dos-Santos DR, Severino FP, Cunha FQ, Guimarães FS (2009) Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol 9:216–222

    Article  CAS  PubMed  Google Scholar 

  • Nikolaeva EP, Cox TC, Flake NM (2015) Osseous characteristics of mice lacking cannabinoid receptor 2 after pulp exposure. J Endod 41:853–857

    Article  PubMed  Google Scholar 

  • Onaivi ES, Ishiguro H, Gong JP, Patel S, Perchuk A, Meozzi PA, Myers L, Mora Z, Tagliaferro P, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Iwasaki S, Arinami T, Teasenfitz L, Uhl GR (2006) Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci 1074:514–536

    Article  CAS  PubMed  Google Scholar 

  • Ossola CA, Surkin PN, Pugnaloni A, Mohn CE, Elverdin JC, Fernandez-Solari J (2012) Long-term treatment with methanandamide attenuates LPS-induced periodontitis in rats. Inflamm Res 61:941–948

    Article  CAS  PubMed  Google Scholar 

  • Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian H, Zhao Y, Peng Y, Han C, Li S, Huo N, Ding Y, Duan Y, Xiong L, Sang H (2010) Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res 45:504–511

    CAS  PubMed  Google Scholar 

  • Sun YX, Xu AH, Yang Y, Zhang JX, Yu AW (2015) Activation of cannabinoid receptor 2 enhances osteogenic differentiation of bone marrow derived mesenchymal stem cells. Biomed Res Int 2015:874982

    PubMed  PubMed Central  Google Scholar 

  • Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13:227–232

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wolf M, Wurm A, Heinemann F, Gerber T, Reichert C, Jäger A, Götz W (2014) The effect of patient age on bone formation using a fully synthetic nanocrystalline bone augmentation material in maxillary sinus grafting. Int J Oral Maxillofac Implants 29:976–983

    Article  PubMed  Google Scholar 

  • Zimmer A (2015) Genetic manipulation of the endocannabinoid system. Handb Exp Pharmacol 231:129–183

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank H. Schrage from the Institute of Molecular Psychiatry as much as I. Bay-Müller K. Reifenrath and J. Marciniak from the Department of Orthodontics, University of Bonn as much as S. Daecke from the Department of Oncology and Hematology, University of Bonn, for technical support.

Author information

Authors and Affiliations

  1. Department of Orthodontics, Medical Faculty, University of Bonn, Bonn, Germany

    Anna Konermann & Andreas Jäger

  2. Department of Oncology and Hematology, University of Bonn, Bonn, Germany

    Stefanie A. E. Held & P. Brossart

  3. Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Bonn, Germany

    Anne Schmöle

Authors
  1. Anna Konermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefanie A. E. Held
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Brossart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Schmöle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Konermann.

Ethics declarations

Conflict of interest

All authors disclose any potential conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Konermann, A., Jäger, A., Held, S.A.E. et al. In vivo and In vitro Identification of Endocannabinoid Signaling in Periodontal Tissues and Their Potential Role in Local Pathophysiology. Cell Mol Neurobiol 37, 1511–1520 (2017). https://doi.org/10.1007/s10571-017-0482-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-017-0482-4

Keywords

Search

Navigation