Turnover of proteoglycans and function of their degradation products in tissue destruction and repair process

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02646
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Aichi Medical University
• Principal Investigator: Watanabe Hideto 愛知医科大学, 付置研究所, 教授 (90240514)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: バーシカン / プロテオグリカン / 創傷治癒 / ノックインマウス / 細胞外マトリックス

Outline of Final Research Achievements

Versican is a large proteoglycan expressed at high levels in tissues during development and remodeling in pathological conditions. Its core protein is cleaved at a region close to the N-terminal end of CSbeta domain by ADAMTS family proteinases. Here, using a CRISPR/Cas9 system, we generated knock-in mice (V1R), which express an ADAMTS cleavage-resistant versican. Some V1R homozygote mice, termed R/R, exhibit syndactyly and organ hemorrhage at late embryonic stages. In wound healing experiments, R/R wound shows versican accumulation and activated TGFbeta-signaling in the early stage, leading to faster healing than wild type wound. The wound region showed higher levels of overall cell proliferation including endothelial cells and myofibroblasts, and increased levels of inflammatory cell infiltration. These results demonstrate that the cleavage site determines versican turnover and that versican plays a central role in the provisional matrix during the wound repair.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

炎症における組織破壊と修復の過程ならびに腫瘍浸潤過程においてECMがダイナミックに変容する際にバーシカンは仮設マトリックスの形成に中心的な役割を果たすといわれている。
本研究成果は、同分子のADAMTS群による分解の意義と代謝産物であるG1断片バーシカインの生体内機能を世界で初めて明示したものとして意義が大きい。G1断片がマトリカインとして機能するという事実は、マトリカインの概念を支持する新たな例といえる。今後はバーシカインの作用機構の詳細を解明し、病態の人為的制御方法の開発に繋げたい。