Elucidation of the switching mechanism for induction of cell death of FGF signal by IL1b in articular cartilage

• Project/Area Number: 17K16678
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KATAGIRI HIROKI 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (50795028)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 変形性膝関節症 / IL1b / FGFレセプター / 疾患修飾型治療薬 / 軟骨細胞 / 軟骨変性機序 / 膝軟骨損傷 / FGF2 / FGFR3 / FGFR１ / IL１ / 炎症 / シグナル伝達

Outline of Final Research Achievements

In defects of 0.9 mm diameter, spontaneous joint surface healing was observed but also upward advancing of the subchondral bone plate at 16 weeks. Larger 1.4 mm diameter defects were critical size, not resulting in successful healing at any time point. Importantly, the articular cartilage surrounding the defects expressed FGF2 and IL1β, but not ACAN and Col2. Chondrocytes cultured in IL1β and FGF2 supplemented media lost the natural fibroblast growth factor receptors - FGFr1/FGFr3 balance and showed decreased viability.
A critical size osteochondral defect was defined as 1.4 mm in diameter in rat. Subchondral bone plate advancement occured rapidly. The articular cartilage surrounding osteochondral defects showed catabolic activity with expression of IL1β, FGF2 and a disturbed FGFr1/FGFr3 balance, potentially initiating a process of early osteoarthritic disease.

Academic Significance and Societal Importance of the Research Achievements

今回我々の研究ではIL1bのFGFレセプターの発現に関与する機序を解明した、シグナルまたはレセプターを個別にブロックすることによりIL1の変性を促進する役割のみを停止し変形性関節症の進行を抑制できると考えられる。また今回の研究はIL1bの直接的なシグナルによる作用ではなく、成長因子のレセプターの変化という間接的な関与を明らかした、IL1bの作用機序のより深い解明に新たな道筋を示した。世界的に変形性膝関節症の抗IL1b薬による治験等が試みられたが有効な報告はなく。今回IL1Bの作用機序を解明したことにより、変形性関節症の新たな疾患修飾型治療薬の開発につながる研究成果であったと考える。

Research Products

• [Journal Article] Reduction of BMP6‐induced bone formation by calcium phosphate in wild‐type compared with nude mice (2019)
  • Author(s): Katagiri Hiroki、Mendes Luis Filipe、Luyten Frank P.
  • Journal Title: Journal of Tissue Engineering and Regenerative Medicine Volume: 印刷中 Issue: 5 Pages: 846-856
  • DOI: 10.1002/term.2837
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Time course analyses of structural changes in the infrapatellar fat pad and synovial membrane during inflammation-induced persistent pain development in rat knee joint. (2019)
  • Author(s): Inomata K, Tsuji K, Onuma H, Hoshino T, Udo M, Akiyama M, Nakagawa Y, Katagiri H, Miyatake K, Sekiya I, Muneta T, Koga H.
  • Journal Title: BMC Musculoskelet Disord. Volume: 20 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s12891-018-2391-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo (2018)
  • Author(s): Mendes L. F.、Katagiri H.、Tam W. L.、Chai Y. C.、Geris L.、Roberts S. J.、Luyten F. P.
  • Journal Title: Stem Cell Research & Therapy Volume: 9 Issue: 1 Pages: 42-55
  • DOI: 10.1186/s13287-018-0787-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Persistent synovial inflammation plays important roles in persistent pain development in the rat knee before cartilage degradation reaches the subchondral bone. (2018)
  • Author(s): Hoshino T, Tsuji K, Onuma H, Udo M, Ueki H, Akiyama M, Abula K, Katagiri H, Miyatake K, Watanabe T, Sekiya I, Koga H, Muneta T.
  • Journal Title: BMC Musculoskelet Disord. Volume: 19 Issue: 1 Pages: 291-291
  • DOI: 10.1186/s12891-018-2221-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Definition of a Critical Size Osteochondral Knee Defect and its Negative Effect on the Surrounding Articular Cartilage in the Rat (2017)
  • Author(s): Katagiri H.、Mendes L.F.、Luyten F.P.
  • Journal Title: Osteoarthritis and Cartilage Volume: 25 Issue: 9 Pages: 1531-1540
  • DOI: 10.1016/j.joca.2017.05.006
  • Peer Reviewed / Open Access
• [Presentation] Underlying mechanisms in the reduction of BMP-induced bone formation in immunocompetent compared to nude mice (2018)
  • Author(s): H Katagiri, Mendes LF, Luyten FP.
  • Organizer: the 12th International BMP
  • Int'l Joint Research