Mechanism of Ectopic Calcification of Dental Pulp Caused by Glycation and Development of Clinical Application Methods

• Project/Area Number: 20K09973
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Osaka University
• Principal Investigator: Miura Jiro 大阪大学, 歯学部附属病院, 助教 (70437383)
• Co-Investigator(Kenkyū-buntansha): 北條 裕信 大阪大学, 蛋白質研究所, 教授 (00209214) ; 清水 真人 大阪大学, 歯学部附属病院, 医員 (70380277)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 糖化 / 異栄養性石灰化 / 加齢 / 老化 / コラーゲン / 血管障害 / 歯髄 / 糖化最終産物 / 歯髄細胞 / 象牙質 / 糖尿病 / 石灰化 / 細胞障害

Outline of Research at the Start

歯髄細胞およびラットを用いた研究で、糖化コラーゲンを用いた培地および高血糖状態のラットにおいて、培地内および歯髄内の基質周囲において石灰化が顕著に起こる現象を確認している。これは、細胞周囲に存在する基質に糖化修飾を加え環境を変えることで、石灰化現象を誘導できる可能性を示唆しており糖化技術を石灰化誘導法に結びつけようという研究は世界的にも前例がない。本研究では、糖化修飾が石灰化へどのような影響を与えているかを多面的に解明し、②糖化ストレスに起因した石灰化を制御することで、必要な部位に石灰化を誘導できることを実証し、基質の糖化に関連した石灰化誘導法による次世代歯科治療法を提案することにある。

Outline of Final Research Achievements

In a rat model of type 2 diabetes, calcification was observed in the dental pulp after 9 weeks of age, and AGEs were deposited in the pulp at the same period. The deposition of S100A8, an inflammatory marker, and the expression of hypoxia-indicating proteins such as HIF-1 alpha suggest that blood flow disorder and hypoxia caused by vascular damage in the pulp may promote dystrophic calcification due to cell damage. These findings may be related to systemic ectopic calcification in patients with severe diabetes mellitus.

Academic Significance and Societal Importance of the Research Achievements

重度糖尿病に罹患すると異所性の石灰化により様々な障害が発生する。これらの発症メカニズムはまだ詳細には分かっておらず、歯科においても糖尿病患者の歯髄内に石灰化物が認められ、原因不明の歯痛が起こるとされるという報告もある。本研究では、糖尿病の主症状の一つである微小血管障害が歯髄内の血流を悪化させることで細胞が低酸素状態によるダメージを受けて異栄養状態におちいり石灰化が起こっていると言うことが分かった。また歯髄内に出来る石灰化物が象牙質に近い組成であると言うことから、老化とともに起きる象牙質の肥厚とも関連があると言うことが示唆された。

Research Products

• [Journal Article] Glycation promotes pulp calcification in Type 2 diabetes rat model (2023)
  • Author(s): Takashima Aoi、Miura Jiro、Sugiyama Keita、Shimizu Masato、Okada Misa、Otani Tomohiro、Nagashima Tadashi、Tsuda Tetsuya、Araki Tsutomu
  • Journal Title: Oral Diseases Volume: - Pages: 593-603
  • DOI: 10.1111/odi.14529
  • Peer Reviewed
• [Journal Article] Effect of tooth temperature on the dentin bonding durability of a self-curing adhesives: The discrepancy between the laboratory setting and inside the mouth (2022)
  • Author(s): YUMITATE Masahiro、MINE Atsushi、HIGASHI Mami、MATSUMOTO Mariko、HAGINO Ryosuke、BAN Shintaro、YAMANAKA Azusa、ISHIDA Masaya、MIURA Jiro、MEERBEEK Bart VAN、ISHIGAKI Shoichi、YATANI Hirofumi
  • Journal Title: Dental Materials Journal Volume: 41 Issue: 2 Pages: 317-322
  • DOI: 10.4012/dmj.2021-184
  • NAID: 130008136550
  • ISSN: 0287-4547, 1881-1361
  • Year and Date: 2022-03-25
  • Peer Reviewed
• [Journal Article] Biological Evaluation of the Effect of Root Canal Sealers Using a Rat Model. (2022)
  • Author(s): Okamoto M, Matsumoto S, Moriyama K, Huang H, Watanabe M, Miura J. Sugiyama K, Hirose Y, Manabu M, Kuriki N, Leprince JG, Takahashi Y, Kawabata S, Hayashi M.
  • Journal Title: Pharmaceutics Volume: 14 Issue: 10 Pages: 2038-2038
  • DOI: 10.3390/pharmaceutics14102038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Does the bonding effectiveness of a fiber post/resin composite benefit from mechanical or chemical treatment? Seven methods for saliva-contaminated surfaces (2022)
  • Author(s): Imai D, Mine A, Ezaki R, Nakatani H, Matsumoto M, Hagino R, Yumitate M, Yamanaka A, Ban S, Miura J, Van Meerbeek B, Higashi M, Yatani H.
  • Journal Title: Journal of Prosthodontic Research Volume: 66 Issue: 2 Pages: 288-295
  • DOI: 10.2186/jpr.JPR_D_21_00015
  • NAID: 130008071537
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of a silane coupling agent and resin primer reinforces bonding effectiveness to a CAD/CAM indirect resin composite block (2021)
  • Author(s): HAGINO Ryosuke、MINE Atsushi、MATSUMOTO Mariko、YUMITATE Masahiro、BAN Shintaro、YAMANAKA Azusa、ISHIDA Masaya、MIURA Jiro、MEERBEEK Bart VAN、YATANI Hirofumi
  • Journal Title: Dental Materials Journal Volume: 40 Issue: 6 Pages: 1445-1452
  • DOI: 10.4012/dmj.2021-083
  • NAID: 130008123565
  • ISSN: 0287-4547, 1881-1361
  • Year and Date: 2021-11-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Back to the multi-step adhesive system: A next-generation two-step system with hydrophobic bonding agent improves bonding effectiveness (2021)
  • Author(s): Yamanaka A, Mine A, Matsumoto M, Hagino R, Yumitate M, Ban S, Ishida M, Miura J, Meerbeek BV, Yatani H.
  • Journal Title: Dental Materials Journal Volume: 40 Issue: 4 Pages: 928-933
  • DOI: 10.4012/dmj.2020-272
  • NAID: 130008069733
  • ISSN: 0287-4547, 1881-1361
  • Year and Date: 2021-07-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Branchiomeric Muscle Development Requires Proper Retinoic Acid Signaling (2021)
  • Author(s): Wang Qi、Xu Lin、Miura Jiro、Saha Mithun Kumar、Uemura Yume、Sandell Lisa L.、Trainor Paul A.、Yamashiro Takashi、Kurosaka Hiroshi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 9 Pages: 596838-596838
  • DOI: 10.3389/fcell.2021.596838
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Do resin core build-ups obtain the benefits of higher bonding ability from direct or indirect technique? (2021)
  • Author(s): Higashi M, Mine A, Matsumoto M, Yumitate M, Hagino R, Ban S, Yamanaka A, Miura J, Minamino T, Van Meerbeek B, Yatani H.
  • Journal Title: Journal of Prosthodontic Research Volume: 65 Issue: 4 Pages: 565-572
  • DOI: 10.2186/jpr.JPR_D_20_00275
  • NAID: 130008104643
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 歯科における老化と糖化 老化に関連する創薬の可能性 (2021)
  • Author(s): 三浦治郎
  • Journal Title: 歯科薬物療法 Volume: 40（3） Pages: 59-64
• [Journal Article] Effects of advanced glycation end products on dental pulp calcification (2021)
  • Author(s): Sugiyama Keita、Miura Jiro、Shimizu Masato、Takashima Aoi、Matsuda Yusuke、Kayashima Hiroki、Okamoto Motoki、Nagashima Tadashi、Araki Tsutomu
  • Journal Title: Oral Diseases Volume: - Issue: 3 Pages: 1-11
  • DOI: 10.1111/odi.13792
  • Peer Reviewed
• [Journal Article] Performance of a Biodegradable Composite with Hydroxyapatite as a Scaffold in Pulp Tissue Repair (2020)
  • Author(s): Motoki Okamoto, Sayako Matsumoto, Ayato Sugiyama ,Kei Kanie ,Masakatsu Watanabe, Hailing Huang, Manahil Ali, Yuki Ito, Jiro Miura, Yujiro Hirose, Koichiro Uto, Mitsuhiro Ebara, Ryuji Kato, Aika Yamawaki-Ogata, Yuji Narita, Shigetada Kawabata, Yusuke Takahashi and Mikako Hayashi
  • Journal Title: polymers Volume: 12 Issue: 4 Pages: 937-937
  • DOI: 10.3390/polym12040937
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Observation of the Epithelial Cell Behavior in the Nasal Septum During Primary Palate Closure in Mice (2020)
  • Author(s): Yamamoto Sayuri、Kurosaka Hiroshi、Miura Jiro、Aoyama Gozo、Sarper Safiye Esra、Oka Ayaka、Inubushi Toshihiro、Nakatsugawa Kohei、Usami Yu、Toyosawa Satoru、Yamashiro Takashi
  • Journal Title: Frontiers in Physiology Volume: 11 Pages: 1-1
  • DOI: 10.3389/fphys.2020.538835
  • Peer Reviewed / Open Access
• [Presentation] 架橋型糖化最終産物（AGEs）と AGEs 阻害薬アラゲブリウムの相互作用の解析 (2022)
  • Author(s): 清水 真人，杉山 敬多，高島 葵，岡田 美佐，三浦 治郎
  • Organizer: 第64回歯科基礎医学会学術大会
• [Presentation] 糖尿病ラットにおける歯髄内血管糖化と阻害法の検討 (2022)
  • Author(s): 岡田 美佐，清水 真人，杉山 敬多，高島 葵，三浦 治郎
  • Organizer: 第64回歯科基礎医学会学術大会
• [Presentation] 糖化ゼラチンスポンジによるラット臼歯部への直接覆髄法の評価 (2022)
  • Author(s): 杉山 敬多，清水 真人，高島 葵，岡田 美佐，三浦 治郎
  • Organizer: 第64回歯科基礎医学会学術大会
• [Presentation] 高血糖状態の歯肉上皮における細胞間接着低下とAGEsとの関与 (2022)
  • Author(s): 生川由貴、柏木洋一郎、富永翔太郎、三浦治郎、村上伸也
  • Organizer: 第157回日本歯科保存学会秋期学術大会
• [Presentation] TAF12, a Member of TFIID Transcription Factor Complex, Contributes to Osteoclast Differentiation and Bone Resorption In Vivo (2020)
  • Author(s): Miyagawa K, Ohta Y, Teramachi J, Miura J, Mark A Subler, John M Chirgwin, Jolene J Windle, G David Rodman, Kurihayra N
  • Organizer: The American society for bone and mineral research 2020
  • Int'l Joint Research
• [Presentation] 根管充填用シーラーが生体組織に与える影響のラット皮下埋入モデルを用いた評価 (2020)
  • Author(s): 松本紗也子、岡本基岐、杉山敬多、三浦治郎、林美加子
  • Organizer: 第20回日本再生医療学会総会