Analyses of crosstalk between RANKL reverse signaling and Wnt signaling pathways in osteoblasts

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H05445
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: The University of Tokyo
• Principal Investigator: Honma Masashi 東京大学, 医学部附属病院, 講師 (60401072)
• Co-Investigator(Kenkyū-buntansha): 鈴木 洋史 東京大学, 医学部附属病院, 教授 (80206523)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: シグナル伝達 / 骨代謝 / 発生・分化

Outline of Final Research Achievements

RANKL reverse signaling was known to promote osteoblast differentiation in vitro, and Wnt canonical pathway was known to promote osteoblast differentiation in vivo. However, roles of Wnt non-canonical pathways and signal crosstalk between Wnt and RANKL reverse signaling remained to be elucidated. Here, we showed that RANKL reverse signaling promotes osteoblast differentiation in vivo. RANKL has a potential as a novel pahrmacological target to enable osteoclast suppression and osteoblast activation simultaneously. We also established a method to evaluate the activation of Wnt signaling pathways quantitatively. Our finsings also suggested that the activation of Wnt/Ca pathway needs the coupling of Fzd and Ca channel at the cell surface.

Free Research Field

骨軟骨代謝学

Academic Significance and Societal Importance of the Research Achievements

RANKL逆シグナル経路が、生体レベルでは骨吸収と骨形成の共役機構の一部として機能している、と言う仮説をサポートする結果が得られると共に、骨粗鬆症などの骨破壊疾患に対する新たな創薬標的になり得ることを示し、臨床的・医学的に意義の大きい成果が得られた。また、非常に複雑なWntシグナル経路の活性化パターンを定量的に評価する手法を確立し、非古典経路の一部であるCa経路の活性化機構に関して、新規の知見が得られ、生物学的にも意義の大きい成果が得られたと考えている。