Molecular mechanisms underlying homeostasis of artiuclar joint

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03799
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Saito Taku 東京大学, 医学部附属病院, 准教授 (30456107)
• Co-Investigator(Kenkyū-buntansha): 山神 良太 東京大学, 医学部附属病院, 助教 (00722191) ; 森 大典 東京大学, 医学部附属病院, 届出研究員 (60835354)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 関節恒常性 / 関節運動 / 滑膜 / 軟骨 / 変形性関節症 / 廃用症候群

Outline of Final Research Achievements

We established a minimized mechanical stress (MMS) model by knee joint immobilization of mice that were suspended by their tails. Histological examination showed synovitis followed by cartilage degeneration. Joint motion could cancel the alteration. Bulk RNA-seq of MMS model mice showed remarkable increases in expression of catabolic factors in synovium and remarkable decreases of matrix proteins in cartilage. On the basis of the cartilage gene expression alterations, Ingenuity Pathway Analysis estimated dozens of upstream cytokines and growth factors, including Spp1 and Il-1β, whose expressions were increased in the MMS model synovium. ScRNA-seq of synovium detected specific subsets among activated fibroblasts and activated macrophages, which expressed cytokines and growth factors responsible for cartilage degeneration. Moreover, ligand-receptor analysis indicated dynamic interactions between the two MMS-specific subsets through these secreted molecules.

Free Research Field

整形外科

Academic Significance and Societal Importance of the Research Achievements

関節を動かすことは関節の機能維持に重要であり、長期間関節を固定すると関節は拘縮し、軟骨は変性するが、そのメカニズムは未だ解明されていない。本研究では、廃用関節で関節変性が起きるメカニズムの一端を初めて明らかにしたという点に意義がある。関節運動は滑膜を介した恒常性維持に不可欠であり、さらに軟骨を含めた関節全体の恒常性維持にも貢献することが示され、今後進みゆく高齢化社会での廃用関節の治療への応用が期待される。