Investigation of roles of the synovial macrophage-derived exosomes on the progression of osteoarthritis and rheumatoid arthritis

• Project/Area Number: 18K09014
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Hokkaido University
• Principal Investigator: Hontani Kazutoshi 北海道大学, 医学研究院, 客員研究員 (10805279)
• Co-Investigator(Kenkyū-buntansha): テルカウィ アラー 北海道大学, 医学研究院, 助教 (00723074)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 変形性関節症 / マクロファージ / 細胞外小胞 / 軟骨細胞 / パイロトーシス / 関節疾患 / 関節リウマチ / エクソソーム / OA / RA / 関節炎

Outline of Final Research Achievements

The objective of this study is to clarify the mechanism of joint disease progression by synovial macrophage derived extracellular vesicles (EVs). Stimulation of chondrocytes with EVs resulted in an elevation in chondrocyte catabolic factors including Matrix metalloproteinase (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs) and pro-inflammatory mediators, leading to cartilage degeneration. In addition, our current results demonstrated that inflammatory macrophages derived EVs increased pyroptosis related molecules in chondrocytes. Our findings indicted that EVs induced chondrocyte pyroptosis, leading to cartilage degradation. This study provides a novel molecular mechanism for the destruction of cartilage in joint diseases and suggests attractive therapeutic target for treatment.

Academic Significance and Societal Importance of the Research Achievements

平均寿命の延伸に伴う要介護者数の増加要因として、変形性関節症をはじめとする関節疾患は上位に位置する。現状、変形性関節症の治療は、薬物療法や装具療法、および人工関節置換術などの手術療法であるが、これらは対症療法の域を脱することはできず、原因療法は未だ存在しない。
申請者は、新たに滑膜マクロファージ由来細胞外小胞を介した軟骨細胞パイロトーシスによる軟骨変性誘導機序を示した。この軟骨細胞のパイロトーシスを抑制する手法は、軟骨変性および関節破壊を抑制することにより、変形性関節症をはじめとする関節疾患の進行を抑制する原因療法の一つとなりうる可能性がある。

Research Products

• [Journal Article] Chondrogenic differentiation of mouse induced pluripotent stem cells using the three‐dimensional culture with ultra‐purified alginate gel (2019)
  • Author(s): Hontani Kazutoshi、Onodera Tomohiro、Terashima Michiyo、Momma Daisuke、Matsuoka Masatake、Baba Rikiya、Joutoku Zenta、Matsubara Shinji、Homan Kentaro、Hishimura Ryosuke、Xu Liang、Iwasaki Norimasa
  • Journal Title: Journal of Biomedical Materials Research Part A Volume: 107 Issue: 5 Pages: 1086-1093
  • DOI: 10.1002/jbm.a.36615
  • NAID: 120006847756
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CCL21/CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults (2019)
  • Author(s): Joutoku Zenta、Onodera Tomohiro、Matsuoka Masatake、Homan Kentaro、Momma Daisuke、Baba Rikiya、Hontani Kazutoshi、Hamasaki Masanari、Matsubara Shinji、Hishimura Ryosuke、Iwasaki Norimasa
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 5165-5165
  • DOI: 10.1038/s41598-019-41621-3
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Inflammatory macrophage-derived extracellular vesicles promote chondrocyte catabolism and cartilage degeneration: An insight into the crosstalk between macrophage and chondrocytes in OA (2021)
  • Author(s): Taku Ebata, M Alaa Terkawi, Gen Matsumae, Hiroaki Kida, Syunichi Yokota, Hend Alhasan, Tomohiro Shimizu, Daisuke Takahashi, Kazutoshi Hontani, Tomohiro Onodera, Ken Kadoya, Norimasa Iwasaki
  • Organizer: Orthopaedic Research Society 2021 Annual Meeting
  • Int'l Joint Research
• [Presentation] Analysis on the Stress Distribution Patterns within the Distal Radioulnar Joint after Ulnar Shortening Osteotomy: Morphological Study with Computed Tomography (2019)
  • Author(s): 2.Kazutoshi Hontani, Daisuke Kawamura, Yuichiro Matsui, Atsushi Urita, Daisuke Momma, Hiroki Hamano, Norimasa Iwasaki
  • Organizer: ORS 2019 Annual Meeting, Austin, Texas, USA
  • Int'l Joint Research
• [Presentation] Impact of ulnar shortening osteotomy on stress distribution patterns within the distal radioulnar joint: Morphologic study with computed tomography (2018)
  • Author(s): 1.Kazutoshi Hontani, Daisuke Kawamura, Yusuke Nagano, Yuichiro Matsui, Atsushi Urita, Yukinori Tsukuda, Daisuke Momma, Hiroki Hamano, Norimasa Iwasaki
  • Organizer: 73rd Annual Meeting of the American Society for Surgery of the Hand. Boston, Massachusetts, USA
  • Int'l Joint Research