Elucidation of the mechanism of venous thromboembolism in spinal ligament ossification model mouse

• Project/Area Number: 19K18449
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Hirosaki University
• Principal Investigator: Ichikawa Nana 弘前大学, 医学部附属病院, 助教 (70837434)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脊柱靭帯骨化症 / 後縦靭帯骨化症 / 静脈血栓塞栓症 / ttwマウス

Outline of Research at the Start

静脈血栓塞栓症(VTE)は脊髄損傷(SCI)後に生じる合併症の１つであり、死に至る危険性があるため、その予防が重要である。過去に我々は脊柱靭帯骨化症患者ではSCI後のVTEの発生頻度が高いことを報告しており、血管形態の異常がその原因である可能性を見出した。本研究の目的は脊柱靭帯骨化症モデルマウスを用いて、血液凝固能、血管形態を経時的に評価し、VTE発生の要因を同定することである。これにより、脊柱靭帯骨化症患者の周術期や外傷後の管理の確率が期待される。また、脊柱靭帯の骨化に先立って新生血管が靭帯組織へ侵入することが報告されており、本研究により骨化症メカニズムの解明につながることが期待される。

Outline of Final Research Achievements

We researched risk factors for venous thromboembolism in ossification of spinal ligament with its model mice (ttw mice). In ttw mice, blood coagulation was extended, vascular wall was thin and much more small blood vessels was seen than control mice. Endothelial cells from ttw had high vasculogenesis capability, and there were much more mesenchymal stem cells around blood vessels in ttw than control. These results contribute to thrombus formation, and suggest that ttw has environment to become thrombosis. Furthermore, this research revealed that high capability of vasculogenesis may contribute to growth of spinal ligament ossification.

Academic Significance and Societal Importance of the Research Achievements

脊柱靭帯骨化症患者では脊髄損傷後の静脈血栓塞栓症の発生頻度が高く、死亡率へ影響している。本研究は脊柱靭帯骨化症における血栓形成に関わる因子を調査し、血栓が生じやすい環境である可能性を見出した。また、骨化症モデルマウスの血管内皮細胞は高い管腔形成能を有し、これが骨化の増大に関与する可能性を見出した。

Research Products

• [Journal Article] Coagulation, Vascular Morphology, and Vasculogenesis in Spinal Ligament Ossification Model Mice (2021)
  • Author(s): Ichikawa Nana、Kumagai Gentaro、Wada Kanichiro、Kudo Hitoshi、Tanaka Sunao、Asari Toru、Liu Xizhe、Sasaki Ayako、Furukawa Ken-Ichi、Ishibashi Yasuyuki
  • Journal Title: Spine Volume: 46 Issue: 15 Pages: E802-E809
  • DOI: 10.1097/brs.0000000000003891
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Blood coagulability, vascular morphology and vasculogenesis capability of spinal ligament ossification model mice (2020)
  • Author(s): Nana Ichikawa
  • Organizer: Orthopaedic Research Association Annual Meeting
  • Int'l Joint Research
• [Presentation] Blood coagulability, vascular morphology and vasculogenesis capability of spinal ligament ossification model mice. (2020)
  • Author(s): Nana Ichikawa
  • Organizer: Orthopaedic Research Society Annual Meeting 2020
  • Int'l Joint Research