Elucidation and application of the mechanism of synergistic healing-promoting effects of amelogenin and teprenone.

• Project/Area Number: 21K21089
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0907:Oral science and related fields
• Research Institution: Kyushu University
• Principal Investigator: Yamato Hiroaki 九州大学, 歯学研究院, 共同研究員 (50906336)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アメロジェニン / テプレノン / GRP78 / 血管新生 / 創傷治癒

Outline of Research at the Start

本研究はアメロジェニン・GRP78複合体がこれらの機能を制御する分子基盤を解明するため、まず、複合体の構造解析により複合体の細胞内移行の機序や生理的機能を解明すること、またテプレノンによりこの複合体の活性増強が可能かを検証することを目的とする。これらの結果をもって、テプレノンとアメロジェニンの複合投与による新しい歯周組織再生療法を開発すると共に、難治性潰瘍の新治療確立に向け研究の展開を図る

Outline of Final Research Achievements

When periodontal ligament cells were stimulated with teprenone, the secretion of angptl4 which has angiogenic activity, and amphiregulin which is a member of the epidermal growth factor family was confirmed. In addition, the production of IL-8, MCP-1, and IL-6, which are angiogenesis-inducing factors, was confirmed in the teprenone + amelogenin combination stimulation group compared with the teprenone single stimulation group. tube formation was induced. In other words, it was suggested that combined stimulation of teprenone and amelogenin strongly promotes periodontal ligament migration, and further induces wound healing and angiogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究によりテプレノン・アメロジェニンによる組織再生のメカニズムが証明されることで、安価かつ安全な歯周組織再生薬によって医療福祉政策に大きく貢献する。さらに、血管新生薬や治癒促進剤等として医科領域まで適応範囲を拡げることができれば、医療費の抑制にも繋がる。実際に、アメロジェニンは褥瘡性潰瘍治療薬(Xelma)として既に用いられているが、テプレノンによる増強作用が証明されれば、これにとって代わる難治性潰瘍治療薬となる可能性がある。

Research Products

• [Journal Article] Extracellular vesicles derived from GMSCs stimulated with TNF-α and IFN-α promote M2 macrophage polarization via enhanced CD73 and CD5L expression. (2022)
  • Author(s): Watanabe Y, Fukuda T, Hayashi C, Nakao Y, Toyoda M, Kawakami K, Shinjo T, Iwashita M, Yamato H, Yotsumoto K, Taketomi T, Uchiumi T, Sanui T, Nishimura F.
  • Journal Title: Sci Rep Volume: 12(1) Issue: 1 Pages: 13344-13344
  • DOI: 10.1038/s41598-022-17692-0
  • Peer Reviewed / Open Access
• [Journal Article] Combined application of geranylgeranylacetone and amelogenin promotes angiogenesis and wound healing in human periodontal ligament cells. (2021)
  • Author(s): Yamato H, Sanui T, Yotsumoto K, Nakao Y, Watanabe Y, Hayashi C, Aihara R, Iwashita M, Tanaka U, Taketomi T, Fukuda T, Nishimura F
  • Journal Title: J Cell Biochem Volume: 122(7) Issue: 7 Pages: 716-730
  • DOI: 10.1002/jcb.29903
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss (2021)
  • Author(s): Nakao Yuki、Fukuda Takao、Zhang Qunzhou、Sanui Terukazu、Shinjo Takanori、Kou Xiaoxing、Chen Chider、Liu Dawei、Watanabe Yukari、Hayashi Chikako、Yamato Hiroaki、Yotsumoto Karen、Tanaka Urara、Taketomi Takaharu、Uchiumi Takeshi、Le Anh D.、Shi Songtao、Nishimura Fusanori
  • Journal Title: Acta Biomaterialia Volume: 122 Pages: 306-324
  • DOI: 10.1016/j.actbio.2020.12.046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adipose-specific C-C motif chemokine ligand (CCL) 19 overexpression drives the mice to both insulin resistance and weight gain (2021)
  • Author(s): Hayashi Masato、Iwashita Misaki、Nishimura Yuki、Shinjo Takanori、Sano Tomomi、Yamashita Akiko、Fukuda Takao、Sanui Terukazu、Asano Tomoichiro、Nishimura Fusanori
  • Journal Title: BMJ Open Diabetes Research & Care Volume: 9 Issue: 1 Pages: e001871-e001871
  • DOI: 10.1136/bmjdrc-2020-001871
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 歯肉幹細胞由来エクソソーム内包miR-1260bによる小胞体ストレス応答制御を介した抗炎症作用. (2021)
  • Author(s): 林千華子、福田隆男、渡邊ゆかり、川上賢太郎、豊田真顕、中尾雄紀、四本かれん、大和寛明、新城尊徳、讃井彰一、西村英紀.
  • Organizer: 第64回春季日本歯周病学会学術大会
• [Presentation] ゲラニルゲラニルアセトンとアメロジェニンの歯周組織再生への複合的効果 (2021)
  • Author(s): 大和寛明、讃井彰一、四本かれん、中尾雄紀、渡邊ゆかり、林千華子、相原良亮、岩下未咲、田中麗、福田隆男、西村英紀
  • Organizer: 2021年度日本歯科保存学会春季学術大会(第154回)
• [Presentation] 歯肉幹細胞由来エクソソーム内包miR-1260bによる小胞体ストレス応答制御を介した歯槽骨吸収抑制作用. (2021)
  • Author(s): 林千華子, 福田隆男, 渡邊ゆかり, 川上賢太郎, 豊田真顕, 中尾雄紀, 四本かれん，大和寛明，新城尊徳，讃井彰一，西村英紀.
  • Organizer: 2021年度日本歯科保存学会秋季学術大会(第155回)
• [Presentation] Exosomes from TNF-α-treated human gingiva-derived MSCs enhance M2 macrophage polarization and inhibit periodontal bone loss. (2021)
  • Author(s): Yuki Nakao, Yukari Watanabe, Chikako Hayashi, Hiroaki Yamato, Karen Yotsumoto, Terukazu Sanui, Takanori Shinjo, Takao Fukuda, Fusanori Nishimura.
  • Organizer: Kyudai Oral Bioscience & OBT Research Center 5th Joint International Symposium
  • Int'l Joint Research
• [Presentation] Exosomal miR-1260b derived from TNF-α-treated hGMSCs inhibits periodontal bone loss by targeting ATF6β-mediated regulation of ER stress. (2021)
  • Author(s): Chikako Hayashi, Takao Fukuda, Yukari Watanabe, Kentaro Kawakami, Masaaki Toyoda, Yuki Nakao, Karen Yotsumoto, Hiroaki Yamato, Takanori Shinjo, Terukazu Sanui, Fusanori Nishimura
  • Organizer: Kyudai Oral Bioscience & OBT Research Center 5th Joint International Symposium
  • Int'l Joint Research