Interaction Between Neural and Non-Neuronal Cells in the Pathogenesis of Periodontitis.

• Project/Area Number: 16K11827
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Periodontology
• Research Institution: Niigata University
• Principal Investigator: Takahashi Naoki 新潟大学, 医歯学総合病院, 助教 (80722842)
• Co-Investigator(Kenkyū-buntansha): 多部田 康一 新潟大学, 医歯学系, 教授 (20401763)
• Research Collaborator: Yamazaki Kazuhisa
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 歯周炎 / 神経ペプチド / TRPチャネル / TRPV1 / 破骨細胞 / 実験的歯周炎モデルマウス / 破骨細胞分化 / 歯周病

Outline of Final Research Achievements

However the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study, we found that Trpv1－/－ mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1－/－ mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin generelated peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrateresistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.

Academic Significance and Societal Importance of the Research Achievements

口腔領域には様々なTRPチャネルタンパクが発現していることが報告されていることから，歯周炎のみならず様々な口腔生理機能や口腔疾患の理解を深めるという学術的意義を持つと考える．さらに，TRPチャネルタンパクの歯周組織における役割が明らかになれば，将来的にはこれらのアゴニストもしくはアンタゴニストを歯周病の予防薬や治療薬として歯磨剤や含嗽剤として応用することが可能である．TRPチャネルタンパクのアゴニストはカプサイシンやメントールなど，自然界に存在しているものが多く，生体親和性が高いために臨床応用しやすく，トランスレーショナルリサーチ実践の即戦力と成り得ることが社会的意義として考えられる．

Research Products

• [Journal Article] β 2-Microglobulin and Neutrophil Gelatinase-Associated Lipocalin, Potential Novel Urine Biomarkers in Periodontitis: A Cross-Sectional Study in Japanese. (2019)
  • Author(s): Mayuka Nakajima、Michihiro Hosojima、Koichi Tabeta、Sayuri Miyauchi、Miki Yamada-Hara、Naoki Takahashi、Haruna Miyazawa、Yumi Matsuda-Matsukawa、Keisuke Sato、Noriko Sugita、Yasutaka Komatsu、Tomomi Ishikawa、Kazuhiro Akiishi、Kazuhisa Yamazaki、Kiminori Kato、Akihiko Saito、Hiromasa Yoshie
  • Journal Title: International Journal of Dentistry Volume: 2019 Pages: 1-10
  • DOI: 10.1155/2019/1394678
  • Peer Reviewed / Open Access
• [Journal Article] Indirect regulation of PCSK9 gene in inflammatory response by Porphyromonas gingivalis infection. (2019)
  • Author(s): Yokoji-Takeuchi M, Tabeta K, Takahashi N, Arimatsu K, Miyazawa H, Matsuda-Matsukawa Y, Sato K, Yamada M, Yamazaki K.
  • Journal Title: Heliyon Volume: 5(1) Issue: 1 Pages: e01111-e01111
  • DOI: 10.1016/j.heliyon.2018.e01111
  • Peer Reviewed / Open Access
• [Journal Article] A bacterial metabolite ameliorates periodontal pathogen-induced gingival epithelial barrier disruption via GPR40 signaling (2018)
  • Author(s): Yamada M, Takahashi N, Matsuda Y, Sato K, Yokoji M, Sulijaya B, Maekawa T, Ushiki T, Mikami Y, Hayatsu M, Mizutani Y, Kishino S, Ogawa J, Arita M, Tabeta K, Maeda T, Yamazaki K
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 9008-9008
  • DOI: 10.1038/s41598-018-27408-y
  • NAID: 120006546008
  • Peer Reviewed / Open Access
• [Journal Article] The anti-inflammatory effect of 10-oxo-trans-11-octadecenoic acid (KetoC) on RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide (2018)
  • Author(s): Sulijaya B.、Takahashi N.、Yamada M.、Yokoji M.、Sato K.、Aoki-Nonaka Y.、Nakajima T.、Kishino S.、Ogawa J.、Yamazaki K.
  • Journal Title: Journal of Periodontal Research Volume: 印刷中 Issue: 5 Pages: 777-784
  • DOI: 10.1111/jre.12564
  • Peer Reviewed
• [Journal Article] Increased serum PCSK9, a potential biomarker to screen for periodontitis, and decreased total bilirubin associated with probing depth in a Japanese community survey (2018)
  • Author(s): Tabeta K.、Hosojima M.、Nakajima M.、Miyauchi S.、Miyazawa H.、Takahashi N.、Matsuda Y.、Sugita N.、Komatsu Y.、Sato K.、Ishikawa T.、Akiishi K.、Yamazaki K.、Kato K.、Saito A.、Yoshie H.
  • Journal Title: Journal of Periodontal Research Volume: 印刷中 Issue: 3 Pages: 446-456
  • DOI: 10.1111/jre.12533
  • Peer Reviewed / Open Access
• [Journal Article] An ENU-induced splice site mutation of mouse Col1a1 causing recessive osteogenesis imperfecta and revealing a novel splicing rescue. (2017)
  • Author(s): Tabeta K, Du X, Arimatsu K, Yokoji M, Takahashi N, Amizuka N, Hasegawa T, Crozat K, Maekawa T, Miyauchi S, Matsuda Y, Ida T, Kaku M, Hoebe K, Ohno K, Yoshie H, Yamazaki K, Moresco EMY, Beutler B
  • Journal Title: Sci. Rep. Volume: 7(1) Issue: 1 Pages: 11717-11717
  • DOI: 10.1038/s41598-017-10343-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. (2017)
  • Author(s): Sato K, Takahashi N, Kato T, Matsuda Y, Yokoji M, Yamada M, Nakajima T, Kondo N, Endo N, Yamamoto R, Noiri Y, Ohno H, Yamazaki K
  • Journal Title: Sci. Rep. Volume: 7(1) Issue: 1 Pages: 6955-6955
  • DOI: 10.1038/s41598-017-07196-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP (2016)
  • Author(s): Takahashi N, Matsuda Y, Sato K, de Jong PR, Bertin S, Tabeta K, Yamazaki K
  • Journal Title: Sci. Rep Volume: 6 Issue: 1 Pages: 29294-29294
  • DOI: 10.1038/srep29294
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation (2016)
  • Author(s): de Jong PR, Taniguchi K, Harris AR, Bertin S, Takahashi N, Duong J, Campos AD, Powis G, Corr M, Karin M, Raz E
  • Journal Title: Nat. Commun Volume: 17 Issue: 1 Pages: 11551-11551
  • DOI: 10.1038/ncomms11551
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. (2016)
  • Author(s): Bertin S, Aoki-Nonaka Y, Lee J, de Jong PR, Kim P, Han T, Yu T, To K, Takahashi N, Boland BS, Chang JT, Ho SB, Herdman S, Corr M, Franco A, Sharma S, Dong H, Akopian AN, Raz E
  • Journal Title: Gut Volume: 2015 Issue: 9 Pages: 310710-310710
  • DOI: 10.1136/gutjnl-2015-310710
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ligature-induced periodontitis in mice induces elevated levels of circulating IL-6 but shows only weak effects on adipose and liver tissues. (2016)
  • Author(s): 3.Matsuda Y, Kato T, Takahashi N, Nakajima M, Arimatsu K, Minagawa T, Sato K, Ohno H, Yamazaki K.
  • Journal Title: Journal of Periodontal Research Volume: 51 Issue: 5 Pages: 639-646
  • DOI: 10.1111/jre.12344
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brazilian propolis mitigates impaired glucose and lipid metabolism in experimental periodontitis in mice. (2016)
  • Author(s): Nakajima M, Arimatsu K, Minagawa T, Matsuda Y, Sato K, Takahashi N, Nakajima T, Yamazaki K.
  • Journal Title: BMC Complement Altern Med Volume: 16 Issue: 1 Pages: 329-337
  • DOI: 10.1186/s12906-016-1305-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] A bacterial metabolite prevents P. gingivalis-induced gingival epithelial barrier disruption in mice model (2019)
  • Author(s): Takahashi N, Yamada M, Sulijaya B, Maeda T, Tabeta K, Yamazaki K
  • Organizer: International Niigata-Taiwan Universities Collaborative Dental Research Symposium 2019
  • Int'l Joint Research
• [Presentation] Interaction Between Neural and Non-Neuronal Cells in the Pathogenesis of Periodontitis. (2019)
  • Author(s): Takahashi N, Matsuda-Matsukawa Y, Sato K, Maeda T, Yamazaki K, Tabeta K
  • Organizer: International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment
  • Int'l Joint Research
• [Presentation] 10-Hydroxy-cis-12-Octadecenoic Acid Ameliorates Gingival Epithelial Barrier Disruption via GPR40-ERK Signaling (2018)
  • Author(s): Takahashi N, Yamada M, Matsuda Y, Sato K, Yokoji M, Sulijaya B, Tabeta K, Nakajima T, Maeda T, Yamazaki K
  • Organizer: 96th General session of the IADR
  • Int'l Joint Research
• [Presentation] Effect of resveratrol on occlusal trauma-induced bone loss in mice. (2017)
  • Author(s): Matsuda Y, Okui T, Minagawa T, Tabeta K, Takahashi N, Sato K, Yamada M, Yokoji M, Nakajima T, Yamazaki K
  • Organizer: 95th General Session & Exhibition of the IADR
  • Place of Presentation: 米国サンフランシスコ
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] A bacterial metabolite ameliorates P. gingivalis-induced gingival epithelial barrier disruption. (2017)
  • Author(s): Yamada M, Takahashi N, Matsuda Y, Sato K, Yokoji M, Tabeta K, Nakajima T, Yamazaki K
  • Organizer: 95th General Session & Exhibition of the IADR
  • Place of Presentation: 米国サンフランシスコ
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] A novel mechanism linking periodontitis and rheumatoid arthritis. (2017)
  • Author(s): Sato K, Takahashi N, Matsuda Y, Yamada M, Yokoji M, Tabeta K, Nakajima T, Yamazaki K
  • Organizer: 95th General Session & Exhibition of the IADR
  • Place of Presentation: 米国サンフランシスコ
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] 歯周病と全身疾患の関連メカニズム―腸内細菌叢を介する新たな仮説― (2017)
  • Author(s): 高橋直紀
  • Organizer: 第71回日本口腔科学会学術集会
• [Presentation] Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP. (2017)
  • Author(s): Takahashi N
  • Organizer: International Symposium on Development of Human Resources in Practical Oral Health and Treatment
  • Int'l Joint Research
• [Presentation] Neuronal TRPV1 activation inhibits alveolar bone resorption via neuropeptide release. (2017)
  • Author(s): Takahashi N, Matsuda Y, Sato K, Tabeta K, Yamazaki K, Maeda T
  • Organizer: 95th General Session & Exhibition of the IADR
  • Int'l Joint Research