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The elucidation of TMJ-OA mechanics and the establishment of medication using NFATc inhibitors

Research Project

Project/Area Number 19K10383
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 57070:Developmental dentistry-related
Research InstitutionHiroshima University

Principal Investigator

Naoto Hirose  広島大学, 病院(歯), 講師 (50611935)

Co-Investigator(Kenkyū-buntansha) 谷本 幸太郎  広島大学, 医系科学研究科(歯), 教授 (20322240)
矢野下 真  広島大学, 医系科学研究科(歯), 助教 (20823199)
國松 亮  広島大学, 医系科学研究科(歯), 准教授 (40580915)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords顎関節症 / 変形性顎関節症 / NFATc / 下顎頭軟骨 / FK506 / 軟骨細胞 / 滑膜細胞 / 炎症 / NFATC / MMP / 軟骨 / 機械的刺激
Outline of Research at the Start

変形性顎関節症(TMJ-OA)は下顎頭軟骨の破壊を生じる疾患で、機械的負荷、外傷、加齢、ストレスらの原因が複雑に絡んでいる。TMJ-OAで吸収した軟骨に治療法および予防法は存在しない。本研究ではカルシニューリン(CaN)- NFATcシグナルを介した、TMJ-OA発症のメカニズムを検討する。さらに軟骨保護に有効なNFATc阻害薬を用いたTMJ-OAの治療法・予防法の確立を最終的な目的とする。

Outline of Final Research Achievements

In vitro experiments, all investigations were performed with ATDC5 condrocytes. FK506 prohibited the expressions of ANGPTL2, COX2, IL1-B, MMP3-13, Adamsts5 when chondrocytes were subject to mechanical stress. The protein expressions of p-ERK, p-P50, p-Akt, p-P38, p-JNK were inhibited by FK506. The protein expressions of NFATc1,3,4 were enhanced, however NFATc2 was suppressed by mechanical stress. FK506 was considered to suppress the inflammation on chondrocytes by inhibition of the NFATc3 phosphorylation. In vivo experiments using TMJ-OA model rats, FK506 didn't work as an unti-inflammatory agent for mandibular condyles.

Academic Significance and Societal Importance of the Research Achievements

本研究により軟骨細胞に対する機械的負荷がCaN-NFATc経路を経由して破壊作用を生じていることが明らかとなった。またCaN阻害剤のFK506の軟骨保護効果の一端が解明された。さらにNFATcの種類ごとの炎症作用との関わりも一部明らかとなりこちらも将来の抗炎症薬・軟骨保護薬としての臨床応用が期待される。
本研究は決定的な治療法および治療薬の存在しない変形性顎関節症を、機械的刺激に関与するメカニクスを制御することにより改善させる治療候補薬の選定に一歩近づいたと言える。またこのメカニクスの解明はあらゆる機械的負荷に伴い発症する疾患への応用が期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (29 results)

All 2021 2020 2019

All Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 2 results) Presentation (21 results) (of which Int'l Joint Research: 6 results)

  • [Journal Article] ANGPTL2 induces synovial inflammation via LILRB22021

    • Author(s)
      Nishiyama S., Hirose N., Yanoshita M., Takano M., Kubo N., Yamauchi Y., Onishi A., Ito S., Sakata S., Kita D., Asakawa-Tanne Y., Tanimoto K.:
    • Journal Title

      Inflammation

      Volume: 44(3) Pages: 1108-1118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] High-frequency Near-infrared Diode Laser Irradiation Suppresses IL-1β-induced Inflammatory Cytokine Expression and NF-κB Signaling Pathways in Human Primary Chondrocytes2021

    • Author(s)
      Sakata S., Kunimastu R., Tsuka Y., Nakatani S., Gunji H., Yanoshita M., Kado I., Ito S., Putranti NAR., RC Prasetya., Hirose N., Tanimoto K.
    • Journal Title

      Lasers Med Sci

      Volume: 37(2) Pages: 1193-1201

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ANGPTL2 Induces Synovial Inflammation via LILRB22020

    • Author(s)
      Sayuri Nishiyama, Naoto Hirose , Makoto Yanoshita , Mami Takano, Naoki Kubo, Yuka Yamauchi, Azusa Onishi, Shota Ito , Shuzo Sakata, Daiki Kita, Yuki Asakawa-Tanne, and Kotaro Tanimoto
    • Journal Title

      Inflammation

      Volume: - Issue: 3 Pages: 1108-1118

    • DOI

      10.1007/s10753-020-01406-7

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress2020

    • Author(s)
      Hirose Naoto、Okamoto Yuki、Yanoshita Makoto、Asakawa Yuki、Sumi Chikako、Takano Mami、Nishiyama Sayuri、Su Shao‐Ching、Mitsuyoshi Tomomi、Kunimatsu Ryo、Tanne Kazuo、Tanimoto Kotaro
    • Journal Title

      Cell Biology International

      Volume: 44 Issue: 4 Pages: 966-974

    • DOI

      10.1002/cbin.11293

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] FAK inhibition protects condylar cartilage under excessive mechanical stress2020

    • Author(s)
      Yanoshita M., Hirose N., Sumi C., Takano M., Nishiyama S., Tsuboi E., Onishi A., Yamauchi Y., Asakawa Y., Kunimatsu R., Tanimoto K
    • Journal Title

      Oral diseases

      Volume: 26(8) Issue: 8 Pages: 1736-1746

    • DOI

      10.1111/odi.13494

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Orthodontic Treatment Combined with Miniscrew Anchorage for an Angle Class II Division 1 Case with Severe Crowding and TMDs2020

    • Author(s)
      Hirose N., Yanoshita M., Onishi A., Yamauchi Y., Nishiyama Y., Takano M., Tsuboi E., Kubo N., Tanimoto K
    • Journal Title

      Dental Research and Oral Health

      Volume: 3(3) Issue: 03

    • DOI

      10.26502/droh.0027

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] High-Frequency Near-Infrared Diode Laser Irradiation Attenuates IL-1β-Induced Expression of Inflammatory Cytokines and Matrix Metalloproteinases in Human Primary Chondrocytes.2020

    • Author(s)
      Sakata S, Kunimatsu R, Tsuka Y, Nakatani A, Hiraki T, Gunji H, Hirose N, Yanoshita M, Putranti NAR, Tanimoto K.
    • Journal Title

      J Clin Med

      Volume: 24 Issue: 3 Pages: 881-881

    • DOI

      10.3390/jcm9030881

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ANGPTL2 Promotes Inflammation via Integrin α5β1 in Chondrocytes.2019

    • Author(s)
      Takano M, Hirose N, Sumi C, Yanoshita M, Nishiyama S, Onishi A, Asakawa Y, Tanimoto K
    • Journal Title

      Cartilage

      Volume: 4 Issue: 2_suppl Pages: 1-13

    • DOI

      10.1177/1947603519878242

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] エストロゲン投与の下顎骨成長への影響と軟骨における変化2021

    • Author(s)
      久保尚毅, 粟田哲也, 廣瀬尚 人, 矢野下真, 高野真美, 西山沙友理, 壷井英里, 北大樹, 大西梓, 山内優佳, 松永萌, 谷本 幸太郎
    • Organizer
      第 80 回日本矯正歯科学会大会・第 5 回国際会議(神奈川)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 高周波近赤外半導体レーザー照射がヒト軟骨細胞の炎症サイトカインに及ぼす影響2021

    • Author(s)
      坂田 修三, 國松亮, 柄優至, 中谷文香, Putranti NAR., 矢野下真, 廣瀬尚人, 谷本幸太郎
    • Organizer
      第 80 回日本矯正歯科学会大会・第 5 回国際会議(神奈川)
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒト滑膜細胞においてレゾルビン D1 は p-38、NF-kβ および AKT シグナルを介して炎症反 応を抑制する2021

    • Author(s)
      矢野下真, 廣瀬尚人, 西山沙由理, 大西梓, 山内優佳, 壷井英里, 久保尚 毅, 北大樹, 麻川由起, 谷本幸太郎
    • Organizer
      第 34 回一般社団法人日本顎関節学会学術大会(東 京)
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒト初代培養軟骨細胞における炎症性サイトカインおよびマトリックスメタロプロテアー ゼの IL-1β誘導性発現に対する高周波近赤外半導体レーザー照射の影響2021

    • Author(s)
      坂田修三, 國松 亮, 柄優至, 中谷文香, Putranti NAR., 矢野下真, 廣瀬尚人, 谷本幸太郎
    • Organizer
      第 34 回日本顎 関節学会学術大会(東京)
    • Related Report
      2021 Annual Research Report
  • [Presentation] 下顎頭の内軟骨性骨化における Semaphorin3A の役割2021

    • Author(s)
      壷井英里, 廣瀬尚人, 麻川由起, 矢 野下真, 大西梓, 高野真実, 西山沙由理, 久保尚毅, 北大樹, 谷本幸太郎
    • Organizer
      第 34 回日本顎関節学会学術大会(東京)
    • Related Report
      2021 Annual Research Report
  • [Presentation] セマフォリン3Aは軟骨において過度な機械的負荷による炎症発現を抑制する2020

    • Author(s)
      廣瀬尚人, 矢野下真, 高野真実, 西山沙由理, 大西梓, 久保尚毅, 麻川由起, 谷本幸太郎
    • Organizer
      第33回日本顎関節学会学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 軟骨に対する過度な機械的負荷時のFAK - MAPKsカスケードによる炎症反応メカニズムの解明2020

    • Author(s)
      矢野下真, 廣瀬尚人, 高野真実, 西山沙由理, 壷井英里, 大西梓, 山内優佳, 久保尚毅, 麻川由起, 谷本幸太郎
    • Organizer
      第33回日本顎関節学会学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 広島大学病院矯正歯科における過去5年間の顎関節症に関する統計調査2020

    • Author(s)
      大西梓, 廣瀬尚人, 麻川由起, 粟田哲也, 矢野下真, 高野真実, 山内優佳, 西山沙由理, 壷井英里,久保尚毅,谷本幸太郎
    • Organizer
      第33回日本顎関節学会学術大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Oral and maxillofacial features of 3 rare congenital diseases uncovered by the Japanese National Health Insurance2020

    • Author(s)
      Onishi A, Hirose N, Yamauchi Y, Yanoshita M, Takano M, Nishiyama S, Kagawa H, Tsuboi E, Kubo N, Tanimoto K
    • Organizer
      The 9th International Orthodontic Congress (Japan)
    • Related Report
      2020 Research-status Report
  • [Presentation] LILRB2 は滑膜細胞において ANGPTL2 により誘導された炎症を制御する2020

    • Author(s)
      西山沙由理,廣 瀬尚人,矢野下真,高野真実,壷井英里,久保尚毅,大西梓,山内優佳,谷本幸太郎
    • Organizer
      第 33 回日本顎関節学会学術大会(京都)
    • Related Report
      2020 Research-status Report
  • [Presentation] An open bite case with temporomandibular disorders caused by a car accident ; a case report2020

    • Author(s)
      Hirose N., Yanoshita M., Onishi A., Yamauchi Y., Nishiyama S., Takano M., Tsuboi E., Kubo N., Tanimoto K.
    • Organizer
      The 9th International Orthodontic Congress, The 12th Asian Pacific Orthodontic Congress, The 79th Annual Meeting of the Japanese Orthodontic Society
    • Related Report
      2020 Research-status Report
  • [Presentation] Familial cases with Hyper-IgE syndrome, Oral/maxillofacial features and Orthodontic treatment plan2020

    • Author(s)
      Yanoshita M., Hirose N., Takano M., Onishi A., Yamauchi Y., Nishiyama S., Kagawa H., Tsuboi E., Kubo N., Asakawa Y., Tanimoto K
    • Organizer
      The 9th International Orthodontic Congress, The 12th Asian Pacific Orthodontic Congress, The 79th Annual Meeting of the Japanese Orthodontic Society (Yokohama)
    • Related Report
      2020 Research-status Report
  • [Presentation] A case of surgical orthodontic treatment for a patient with osteogenesis imperfecta2020

    • Author(s)
      Takano M., Asakawa Y., Hirose N., Tsuboi E., Nakatani A., Kunimatsu R., Tanimoto K
    • Organizer
      The 9th International Orthodontic Congress, The 12th Asian Pacific Orthodontic Congress, The 79th Annual Meeting of the Japanese Orthodontic Society (Yokohama)
    • Related Report
      2020 Research-status Report
  • [Presentation] Role of Semaphorin3A in endochondral ossification of mandibular condyle2020

    • Author(s)
      Tsuboi E., Asakawa Y., Hirose N., Yanoshita M., Takano M., Nishiyama S., Kubo N., Onishi A., Yamauchi Y., Tanimoto K
    • Organizer
      The 9th International Orthodontic Congress, The 12th Asian Pacific Orthodontic Congress, The 79th Annual Meeting of the Japanese Orthodontic Society (Yokohama)
    • Related Report
      2020 Research-status Report
  • [Presentation] 顎関節症に対する矯正歯科の役割~臨床・研究の両面から~2020

    • Author(s)
      廣瀬尚人
    • Organizer
      第 33 回日本顎関 節学会学術大会(京都)
    • Related Report
      2020 Research-status Report
  • [Presentation] Semaphorin3A Inhibits Inflammation in Chondrocytes under Excessive Mechanical Stress.2019

    • Author(s)
      Hirose N., Sumi C., Yanoshita M., Takano M., Nishiyama S., Tsuboi E., Onishi A., Yamauchi Y., Asakawa Y., Tanimoto K
    • Organizer
      The 97th General Session of International Association for Dental Research (Vancouver)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Anti - inflammatory effects of FAK inhibitor on condylar cartilage under excessive mechanical stress2019

    • Author(s)
      Yanoshita M., Hirose N., Takano M., Sumi C., Nishiyama S., Tsuboi E., Asakawa Y., Onishi A., Yamauchi Y., Tanimoto K.
    • Organizer
      The 97th General Session of International Association for Dental Research (Vancouver),
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 軟骨細胞におけるANGPTL2による炎症促進メカニズムの解明2019

    • Author(s)
      高野真実, 廣瀬尚人, 矢野下真, 西山沙由理, 壷井英里, 大西梓, 山内優佳, 麻川由起, 谷本幸太郎
    • Organizer
      第32回顎関節学会総会・学術大会(東京)第6回アジア顎関節学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 下顎頭軟骨への過度な圧迫負荷付与時のFAK阻害剤の抗炎症効果-器官培養法を用いた検討-2019

    • Author(s)
      矢野下真, 廣瀬尚人, 高野真実, 西山沙由理, 大西梓, 山内優佳, 壷井英里, 麻川由起, 谷本幸太郎
    • Organizer
      第32回顎関節学会総会・学術大会(東京)第6回アジア顎関節学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 機械的刺激による軟骨破壊のメカニクス 顎関節症治療薬候補物質の探索2019

    • Author(s)
      廣瀬尚人
    • Organizer
      第32回顎関節学会総会・学術大会(東京)第6回アジア顎関節学会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 顎関節治療の新たな知見2019

    • Author(s)
      廣瀬尚人
    • Organizer
      香川県保険医協会主催医科歯科合同セミナー(香川)
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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