Integrated understanding of Del-1 functions on osteobiology and Inflammation

• Project/Area Number: 17KK0165
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Periodontology
• Research Institution: Niigata University
• Principal Investigator: Maekawa Tomoki 新潟大学, 医歯学系, 研究教授 (50625168)
• Project Period (FY): 2018 – 2020
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
• Keywords: DEL-1 / 骨吸収 / 骨再生 / 歯周炎 / 粘膜疾患 / 骨免疫 / 抗炎症作用 / 肺炎 / 破骨細胞 / 歯周病 / 抗炎症 / 粘膜炎 / 免疫 / 粘膜免疫 / 骨代謝 / 抗炎症物質 / 骨免疫学 / 歯周病治療学 / 骨代謝学 / Del-1 / 炎症性疾患 / トランスレーショナルリサーチ / 抗炎症分子 / 好中球

Outline of Final Research Achievements

DEL-1 is constitutively produced by osteoclasts and vascular endothelial cells, and has been found to have a variety of functions, including inhibition of osteoclasts, effects on bone metabolism and mesenchymal stem cells, and induction of regulatory T cells. It is highly possible that DEL-1 is related to the aging process, as it decreases with inflammation and aging. Studies on two mucosal diseases, periodontitis and pneumonia, have revealed the mechanism of action of DEL-1 on osteoclasts and osteoblasts and the regulation of DEL-1 expression. Collaborative research with overseas researchers who have various disease models for DEL-1 has led to a dramatic development of our research.

Academic Significance and Societal Importance of the Research Achievements

本研究成果によって，歯周炎および肺炎に対する新しい治療戦略を提示することができた．歯周炎においては，歯の周りの組織の炎症により重度な骨吸収が起き，最終的には歯が抜けてしまう．本研究で着目したDEL-1を歯周炎組織に誘導することが可能となれば，歯周炎を抑制するだけでなく，歯周炎によって失われた骨も再生可能である．さらにDEL-1による抗炎症および再生効果は，歯周炎と同様な粘膜疾患である肺炎にも応用することが可能となり，ポスト新型コロナ肺炎での破壊された肺組織の再生にDEL-1が寄与しているデータを得ることができた．今後は，DEL-1による組織再生の詳細なメカニズム解析を行い，臨床への展開を図る．

Research Products

• [Int'l Joint Research] ペンシルベニア大学(米国) (2019)
  • Year and Date: 2019-07-06
• [Journal Article] Effects of Erythromycin on Osteoclasts and Bone Resorption via DEL-1 Induction in Mice (2021)
  • Author(s): Tamura Hikaru、Maekawa Tomoki、Domon Hisanori、Hiyoshi Takumi、Hirayama Satoru、Isono Toshihito、Sasagawa Karin、Yonezawa Daisuke、Takahashi Naoki、Oda Masataka、Maeda Takeyasu、Tabeta Koichi、Terao Yutaka
  • Journal Title: Antibiotics Volume: 10 Issue: 3 Pages: 312-312
  • DOI: 10.3390/antibiotics10030312
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of Experimental Ligature-Induced Periodontitis Model in Mice (2020)
  • Author(s): Tamura Hikaru、Maekawa Tomoki、Hiyoshi Takumi、Terao Yutaka
  • Journal Title: Methods Mol Biol Volume: 1 Pages: 237-250
  • DOI: 10.1007/978-1-0716-0939-2_23
  • ISBN: 9781071609385, 9781071609392
  • Peer Reviewed
• [Journal Article] Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1 (2020)
  • Author(s): Maekawa Tomoki、Tamura Hikaru、Domon Hisanori、Hiyoshi Takumi、Isono Toshihito、Yonezawa Daisuke、Hayashi Naoki、Takahashi Naoki、Tabeta Koichi、Maeda Takeyasu、Oda Masataka、Ziogas Athanasios、Alexaki Vasileia Ismini、Chavakis Triantafyllos、Terao Yutaka、Hajishengallis George
  • Journal Title: JCI Insight Volume: 5 Issue: 15 Pages: 136706-136706
  • DOI: 10.1172/jci.insight.136706
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The secreted protein DEL-1 activates a β3 integrin-FAK-ERK1/2-RUNX2 pathway and promotes osteogenic differentiation and bone regeneration. (2020)
  • Author(s): Yuh DY, Maekawa T, Li X, Kajikawa T, Bdeir K, Chavakis T, Hajishengallis G.
  • Journal Title: The Journal of Biological Chemistry Volume: In press Issue: 21 Pages: 7261-7273
  • DOI: 10.1074/jbc.ra120.013024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1 (2020)
  • Author(s): Ziogas Athanasios、Maekawa Tomoki、Wiessner Johannes R.、Le Thi Trang、Sprott David、Troullinaki Maria、Neuwirth Ales、Anastasopoulou Vasiliki、Grossklaus Sylvia、Chung Kyoung-Jin、Sperandio Markus、Chavakis Triantafyllos、Hajishengallis George、Alexaki Vasileia Ismini
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 5 Pages: 1214-1224
  • DOI: 10.4049/jimmunol.1900746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective effect of hinokitiol against periodontal bone loss in ligature-induced experimental periodontitis in mice (2020)
  • Author(s): Hiyoshi Takumi、Domon Hisanori、Maekawa Tomoki、Yonezawa Daisuke、Kunitomo Eiji、Tabeta Koichi、Terao Yutaka
  • Journal Title: Archives of Oral Biology Volume: 112 Pages: 104679-104679
  • DOI: 10.1016/j.archoralbio.2020.104679
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antibacterial activity of hinokitiol against both antibiotic‐resistant and ‐susceptible pathogenic bacteria that predominate in the oral cavity and upper airways (2019)
  • Author(s): Domon Hisanori、Hiyoshi Takumi、Maekawa Tomoki、Yonezawa Daisuke、Tamura Hikaru、Kawabata Shigetada、Yanagihara Katsunori、Kimura Osamu、Kunitomo Eiji、Terao Yutaka
  • Journal Title: Microbiology and Immunology Volume: 63 Issue: 6 Pages: 213-222
  • DOI: 10.1111/1348-0421.12688
  • NAID: 40021941640
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Complement-Dependent Mechanisms and Interventions in Periodontal Disease (2019)
  • Author(s): Hajishengallis G, Kajikawa T, Hajishengallis E, Maekawa T, Reis ES, Mastellos DC, Yancopoulou D, Hasturk H, Lambris JD.
  • Journal Title: Frontiers in Immunology Volume: 10
  • DOI: 10.3389/fimmu.2019.00406
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin‐dependent neutrophil lysis (2019)
  • Author(s): Hiyoshi Takumi、Domon Hisanori、Maekawa Tomoki、Nagai Kosuke、Tamura Hikaru、Takahashi Naoki、Yonezawa Daisuke、Miyoshi Tomohiro、Yoshida Akihiro、Tabeta Koichi、Terao Yutaka
  • Journal Title: Microbiology and Immunology Volume: 63 Issue: 3-4 Pages: 100-110
  • DOI: 10.1111/1348-0421.12672
  • NAID: 40021899825
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peptides from rice endosperm protein restrain periodontal bone loss in mouse model of periodontitis (2019)
  • Author(s): Tamura Hikaru、Maekawa Tomoki、Domon Hisanori、Hiyoshi Takumi、Yonezawa Daisuke、Nagai Kosuke、Ochiai Akihito、Taniguchi Masayuki、Tabeta Koichi、Maeda Takeyasu、Terao Yutaka
  • Journal Title: Archives of Oral Biology Volume: 98 Pages: 132-139
  • DOI: 10.1016/j.archoralbio.2018.11.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection (2019)
  • Author(s): Nagai Kosuke、Domon Hisanori、Maekawa Tomoki、Hiyoshi Takumi、Tamura Hikaru、Yonezawa Daisuke、Habuka Rie、Saitoh Akihiko、Terao Yutaka
  • Journal Title: Vaccine Volume: 37 Issue: 1 Pages: 160-168
  • DOI: 10.1016/j.vaccine.2018.11.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from children with acute otitis media in Japan from 2014 to 2017 (2019)
  • Author(s): Nagai Kosuke、Kimura Osamu、Domon Hisanori、Maekawa Tomoki、Yonezawa Daisuke、Terao Yutaka
  • Journal Title: Journal of Infection and Chemotherapy Volume: 25 Issue: 3 Pages: 229-232
  • DOI: 10.1016/j.jiac.2018.08.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae (2018)
  • Author(s): Domon Hisanori、Maekawa Tomoki、Yonezawa Daisuke、Nagai Kosuke、Oda Masataka、Yanagihara Katsunori、Terao Yutaka
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 62 Issue: 11
  • DOI: 10.1128/aac.00161-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gingival Exudatome Dynamics Implicate Inhibition of the Alternative Complement Pathway in the Protective Action of the C3 Inhibitor Cp40 in Nonhuman Primate Periodontitis (2018)
  • Author(s): Bostanci N, Bao K, Li X, Maekawa T, Grossmann J, Panse C, Briones RA, Resuello RRG, Tuplano JV, Garcia CAG, Reis ES, Lambris JD, Hajishengallis G
  • Journal Title: Journal of Proteome Research Volume: 17 Issue: 9 Pages: 3153-3175
  • DOI: 10.1021/acs.jproteome.8b00263
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-like Receptors and Cytokines in Pneumococcal Pneumonia (2018)
  • Author(s): Domon Hisanori、Nagai Kosuke、Maekawa Tomoki、Oda Masataka、Yonezawa Daisuke、Takeda Wataru、Hiyoshi Takumi、Tamura Hikaru、Yamaguchi Masaya、Kawabata Shigetada、Terao Yutaka
  • Journal Title: Front Immunol Volume: 印刷中 Pages: 732-732
  • DOI: 10.3389/fimmu.2018.00732
  • 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
• [Presentation] 歯学研究の今昔と次世代研究 DEL-1分子誘導による抗炎症および骨形成メカニズムの解明 (2020)
  • Author(s): 前川 知樹
  • Organizer: 第62回歯科基礎医学会学術大会，鹿児島（Web開催）
• [Presentation] マウス歯牙結紮歯周炎モデルにおけるヒノキチオールの骨吸収抑制作用の解析 (2020)
  • Author(s): 日吉 巧，土門久哲，前川知樹，田村 光，米澤大輔，國友栄治，寺尾 豊，多部田康一
  • Organizer: 第63回春季日本歯周病学会学術大会，郡山（Web開催）
• [Presentation] 宿主由来エラスターゼはHLAクラスII発現を抑制する (2020)
  • Author(s): 土門久哲，前川知樹，寺尾 豊
  • Organizer: 第62回歯科基礎医学会学術大会，鹿児島（Web開催）
• [Presentation] ヒノキチオールの抗菌活性および抗炎症作用によるマウス歯牙結紮歯周炎モデル骨吸収抑制作用の解析 (2020)
  • Author(s): 日吉 巧，土門久哲，前川知樹，田村 光，國友栄治，寺尾 豊
  • Organizer: 第62回歯科基礎医学会学術大会，鹿児島（Web開催）
• [Presentation] エリスロマイシンによるDel-1誘導を介した骨代謝の制御 (2020)
  • Author(s): 田村 光，前川知樹，土門久哲，日吉 巧，前田健康，寺尾 豊
  • Organizer: 第62回歯科基礎医学会学術大会，鹿児島（Web開催）
• [Presentation] エリスロマイシンによるDEL-1誘導を介した破骨細胞の制御 (2020)
  • Author(s): 田村 光，前川知樹，土門久哲，日吉 巧，磯野俊仁，米澤大輔，前田健康，寺尾 豊，多部田康一
  • Organizer: 第63回秋季歯周病学会学術大会, 石川（Web開催）
• [Presentation] 好中球エラスターゼによる歯周炎重症化メカニズム解析 (2020)
  • Author(s): 日吉 巧，土門久哲， 前川知樹，田村 光，磯野俊仁，寺尾 豊，多部田康一
  • Organizer: 第63回秋季歯周病学会学術大会, 石川（Web開催）
• [Presentation] 宿主由来エラスターゼは HLA クラス II 発現を抑制する (2020)
  • Author(s): 土門 久哲，前川 知樹，寺尾 豊
  • Organizer: 第63回秋季歯周病学会学術大会, 石川（Web開催）
• [Presentation] シンポジウム「オーラルエイジングを科学し全身の健康を目指す」歯周組織のアンチエイジングから歯周病を制御する (2019)
  • Author(s): 前川 知樹
  • Organizer: 第19回日本抗加齢医学会総会，横浜
• [Presentation] Genetic and Intervention Studies Implicating Keystone Pathogens and Del-1 as Major Targets for the Treatment of Periodontitis. (2019)
  • Author(s): Maekawa T
  • Organizer: International Collaborative Symposium on Development of Human Resources in Practical Oral Health and Treatment
  • Int'l Joint Research / Invited
• [Presentation] Del-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in periodontitis, rheumatoid arthritis and pneumonia of non-human primates (2019)
  • Author(s): Maekawa T
  • Organizer: 6th Symposium of the Smart-Aging Research Center, Tohoku University
  • Invited
• [Presentation] 内因性抗炎症分子Del-1を介したマクロライド系抗菌薬の新作用機序 (2019)
  • Author(s): 前川知樹
  • Organizer: 第4回日本骨免疫学会ウインターセミナー，軽井沢
• [Presentation] 内因性抗炎症Del-1分子による炎症性骨破壊―歯周病とリウマチ―の治療戦略 (2018)
  • Author(s): 前川知樹
  • Organizer: 第60回歯科基礎医学会学術大会，福岡
• [Presentation] Del-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in periodontitis (2018)
  • Author(s): Maekawa T
  • Organizer: Niigata U-CU Seminar in Periodontal Research. Chulalongkorn University, Bangkok, Thailand
  • Invited
• [Presentation] Local regulator Del1 inhibits bone-resorption via suppression of Wnt5a-Ror2 signaling (2018)
  • Author(s): Maekawa T, Domon H, Kobayashi Y, Nagai K, Yonezawa D, Terao Y, Maeda T, Hajishengallis G
  • Organizer: 96th General Session & Exhibition of the IADR, London, England
  • Int'l Joint Research
• [Presentation] Local regulator Del1 inhibits bone-resorption via suppression of Wnt5a-Ror2 signaling axis (2018)
  • Author(s): Maekawa T, Kobayashi Y, Domon H, Tamura H, Hiyoshi T, Maeda T, Terao Y, Hajishengallis G
  • Organizer: ASBMR 2018 Annual Meeting, Montreal, Canada
  • Int'l Joint Research
• [Presentation] 内因性抗炎症分子Del-1分子誘導による炎症性骨破壊の新規治療戦略 (2018)
  • Author(s): 前川知樹，小林泰浩，土門久哲，田村 光，日吉 巧，永井康介，寺尾 豊，前田健康
  • Organizer: 第４回日本骨免疫学会，沖縄
• [Presentation] 内因性抗炎症Del-1分子誘導による炎症性骨破壊の新規治療戦略 (2018)
  • Author(s): 前川知樹
  • Organizer: 秋季日本歯周病学会学術大会，大阪
• [Presentation] Keystone細菌と炎症性骨破壊制御による歯周病治療への展開 (2018)
  • Author(s): 前川知樹
  • Organizer: 21世紀を明るく科学する会，静岡
• [Presentation] 内因性抗炎症分子Del-1を介したマクロライド系抗菌薬の新作用機序 (2018)
  • Author(s): 前川知樹，土門久哲，寺尾 豊
  • Organizer: 第25回マクロライド新作用研究会，東京
• [Book] BIO Clinica DEL-1分子誘導による炎症性骨破壊の新規治療戦略 (2020)
  • Author(s): 前川 知樹
  • Total Pages: 5
  • Publisher: 北隆館
• [Remarks] 新潟大学大学院医歯学総合研究科 高度口腔機能教育研究センターホームページ
  • URL: https://www.caos-niigata-univ.net/
• [Remarks] DEL-1を介したエリスロマイシンの抗炎症メカニズムを解明しました
  • URL: https://www.niigata-u.ac.jp/news/2020/75897/
• [Remarks] 新潟大学医歯学総合研究科 高度口腔機能教育研究センター
  • URL: http://www.caos-niigata-univ.net/
• [Remarks] 新潟大学高度口腔機能教育研究センター
  • URL: http://www.caos-niigata-univ.net/