Establishment of effective treatment for temporomandibular joint disorders with Docosahexaenoic acid (DHA) and Resolvin

• Project/Area Number: 19K21397
• Project/Area Number (Other): 18H06310 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0907:Oral science and related fields
• Research Institution: Hiroshima University
• Principal Investigator: Yanoshita Makoto 広島大学, 病院(歯), 歯科診療医 (20823199)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: レゾルビンD1 / 機械的負荷 / 炎症 / 軟骨 / 滑膜 / 不飽和脂肪酸 / 顎関節症 / レゾルビン / レゾルビンD１ / 軟骨細胞 / 顎関節

Outline of Research at the Start

顎関節症は日本国民の約20%以上の罹患が報告されている難治性疾患であり、いまだ根本的治療法は見つかっていない。レゾルビンD1は魚油に含まれる不飽和脂肪酸の代謝産物で、抗炎症効果を有すると報告されている。我々はこれまで細胞伸展装置および作製したラット下顎頭高負荷モデルを用い、過度な機械的負荷による軟骨の炎症反応について細胞・組織レベルでの研究を行ってきた。そこで本研究はこれらのモデルを用い、顎関節炎に対するレゾルビンD1の抗炎症作用とそのメカニズムを解明し、顎関節軟骨保護および修復作用についての検討を行う。また、これらを顎関節症患者の治療に応用し、新規治療法を確立することを究極の目標とする。

Outline of Final Research Achievements

Experiment 1 (in vitro) : Cyclic tensile strain (CTS) induced gene expression of inflammation-related factors and MMPs and treatment with Resolvin D1 suppressed CTS-induced expression of pro-inflammatory cytokine genes. In addition, western blot analysis indicated that Resolvin D1 might suppress inflammation via integrin-FAK signal.
Experiment 2 (in vivo, ex vivo) : Gene expression of inflammation-related factors and MMPs was increased in TMJ rat model. However, injection of Resolvin D1 and oral administration of DHA to rats was forced to interrupt the experiment due to cost problems. Therefore, as an alternative, we used ex vivo organ culture model. and Resolvin D1 suppressed inflammation at the gene level. We plan to continue further studies.

Academic Significance and Societal Importance of the Research Achievements

申請者らは、ω3不飽和脂肪酸（ドコサヘキサエン酸)の代謝産物であるレゾルビンの軟骨における機能に着目し検討を行った。軟骨細胞に機械的刺激を付与したときに生じる炎症関連因子の発現（IL1-β、TNFα、COX2、MMP3および13）はレゾルビンの添加により有意に抑制された。この結果は変形性顎関節症のような顎関節疾患の治療法へとつながる貴重な知見だと考える。

Research Products

• [Journal Article] Protective effects of cilengitide on inflammation in chondrocytes under excessive mechanical stress (2020)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elucidation of the inflammatory mechanism of mandibular cartilage development and the establishment of a prevention method for PCR using Sema3A Download Article: Download (PDF 362 kb) (2019)
  • Author(s): Hirose, Naoto; Chikako, Sumi; Yanoshita, Makoto; Nishiyama, Sayuri; Tsuboi, Eri
  • Journal Title: Impact Volume: Number 4 Issue: 4 Pages: 67-69
  • DOI: 10.21820/23987073.2019.4.67
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Anti - inflammatory effects of FAK inhibitor on condylar cartilage under excessive mechanical stress (2019)
  • Author(s): Yanoshita Makoto、Hirose Naoto、Takano Mami、Sumi Chikako、Nishiyama Sayuri、Tsuboi Eri、Asakawa Yuki、Onishi Azusa、Yamauchi Yuuka、Tanimoto Kotaro
  • Organizer: The 97th General Session of International Association for Dental Research（Vancouver）, 2019.
  • Int'l Joint Research
• [Presentation] Semaphorin3A Inhibits Inflammation in Chondrocytes under Excessive Mechanical Stress (2019)
  • Author(s): Hirose Naoto、Yanoshita Makoto、Takano Mami、Sumi Chikako、Nishiyama Sayuri、Tsuboi Eri、Asakawa Yuki、Onishi Azusa、Yamauchi Yuuka、Tanimoto Kotaro
  • Organizer: The 97th General Session of International Association for Dental Research（Vancouver）, 2019.
  • Int'l Joint Research
• [Presentation] Effects of FAK inhibitor on condylar cartilage under the excessive mechanical stress in organ culture model (2019)
  • Author(s): Yanoshita Makoto、Hirose Naoto、Takano Mami、Sumi Chikako、Nishiyama Sayuri、Tsuboi Eri、Asakawa Yuki、Onishi Azusa、Yamauchi Yuuka、Tanimoto Kotaro
  • Organizer: The 32nd Annual Meeting of the Japanese Society for Temporomandibular Joint, The 6th Asian Academy congress for Temporomandibular Joint（Tokyo）, 2019.
  • Int'l Joint Research
• [Presentation] ANGPTL2 promotes inflammation via integrin α5β1 in chondrocytes (2019)
  • Author(s): Takano Mami、Yanoshita Makoto、Hirose Naoto、Nishiyama Sayuri、Tsuboi Eri、Onishi Azusa、Yamauchi Yuuka、Asakawa Yuki、Tanimoto Kotaro
  • Organizer: The 32nd Annual Meeting of the Japanese Society for Temporomandibular Joint, The 6th Asian Academy congress for Temporomandibular Joint（Tokyo）, 2019.
  • Int'l Joint Research