Production of humanized mouse models for chronic recurrent multifocal osteomyelitis and antiinflammatory drug development

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06041
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Tokai University
• Principal Investigator: Abe Koichiro 東海大学, 医学部, 准教授 (90294123)
• Co-Investigator(Kenkyū-buntansha): 荒木 喜美 熊本大学, 生命資源研究・支援センター, 教授 (90211705)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 自己炎症性症候群 / 疾患モデルマウス / Srcファミリーキナーゼ / Ali18マウス / 自己炎症性骨疾患

Outline of Final Research Achievements

Chronic recurrent multifocal osteomyelitis　（CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. In analysis of murine Ali18 mutant strain which shows autoinflammatory arthritis in peripheral limb, we identified a missense mutation in Fgr, a member of Src family kinases.　Fgr plays an important role in lymphocyte and myeloid cell lineages. Here we introduced human FGR missense mutations identified in CRMO into the murine Fgr locus in ES cells, and ES cell-derived mutant strain were established. Although these FGR homozygous mutant do not show peripheral arthritis for one year after their birth, enlarged spleens were observed in some of mutant mice. Therefore, we concluded the human FGR mutations do not contribute to autoinflammation in bone but do to develop lymphoma, which may modify or control autoinflammation strength.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

慢性再発性多発性骨髄炎（CRMO）は指定難病であり、現在までに確立された診断方法や治療法が少ない。このCRMOの原因遺伝子のひとつとして、マウス変異系統の解析よりSrcファミリーのFgrチロシンキナーゼが同定された。それと同時にCRMOの患者において、FGRタンパクのアミノ酸置換を起こす２つの多型も見つかった。これらのFGRで見つかった多型（変異）の機能を探るため、変異型FGRをマウスFgr遺伝子座に導入したマウスを作製して解析を行った。その結果、これらのマウスは自己炎症性の骨病態を示さなかったことから、CRMOで見つかった変異は自己炎症の修飾効果を担い、直接の原因ではないことが示唆された。