Roles of an atypical Wnt receptor, Ryk, for bone remodeling(Fostering Joint International Research)

• Project/Area Number: 15KK0356
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Functional basic dentistry
• Research Institution: Matsumoto Dental University
• Principal Investigator: Nakamichi Yuko 松本歯科大学, 総合歯科医学研究所, 講師 (20350829)
• Research Collaborator: Major Michael Ben University of North Carolina at Chapel Hill, Lineberger Cancer Center, Associate Professor ; Udagawa Nobuyuki 松本歯科大学, 歯学部, 教授
• Project Period (FY): 2016 – 2018
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
• Keywords: プロテオーム / ゲノム / シグナル伝達

Outline of Final Research Achievements

WNT signaling controls myriad biological processes throughout life of all animals. Ryk is a member of the Wnt receptors and does not belong to the conventional classification of the Wnt signal transduction. Little is known about its mechanism of action. Ryk may be involved in Wnt-regulated processes in bone remodeling. In this study, we elucidated roles of Ryk for bone and mineral metabolism by using Ryk conditional KO (cKO) mice lines that are established in our laboratory. Using two mesenchymal-specific Ryk cKO mice, we confirmed that Ryk enhances bone formation. In addition to the analysis of Ryk cKO mice, we tried to identify osteotropic downstream molecules of Wnt3a (one of the Ryk ligands), utilizing the analysis platform developed by the oversea collaborator, the Major laboratory (UNC-CH). To this end, we set up a functional genomic screening with a gain-of-function approach (called Crispr-A) and developed a sensitive reporter system. We also performed Phospho-MS analysis.

Academic Significance and Societal Importance of the Research Achievements

最近、Wntシグナルが活性化している悪性腫瘍において、抗腫瘍免疫活性がWntシグナルにより抑制されているという報告が多数存在する。これはRyk が、癌治療の有望な分子標
的であることを示す。本研究ではゲノムワイドスクリーニングの系の立ち上げに成功した。今後、Ryk シグナルのエフェクター分子が同定されれば、基礎生物学のブレイクスルーとなる。このエフェクター分子は骨形成促進薬となり得るばかりか、骨や神経の再生医療、がん治療、および口蓋裂などの歯科領域治療における分子標的にもなる可能性がある。将来的には、この分子標的を利用した新規治療法の開発がもたらされることが期待される。

Research Products

• [Int'l Joint Research] ノースカロライナ大学チャペルヒル校(米国) (2017)
  • Year and Date: 2017-09-05
• [Journal Article] WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop (2019)
  • Author(s): Agajanian MJ, Walker MP, Axtman AD, Ruela-de-Sousa RR, Serafin DS, Rabinowitz AD, Graham DM, Ryan MB, Tamir T, Nakamichi Y, Gammons MV, Bennett JM, Counago RM, Drewry DH, Elkins JM, Gileadi C, Gileadi O, Godoi PH, Kapadia N, Muller, Santiago A, Sorrell FJ, Wells CI, Fedorov O, Willson TM, Zuercher WJ, Major MB.
  • Journal Title: Cell Reports Volume: 26
  • DOI: 10.1016/j.celrep.2018.12.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mechanisms involved in bone resorption regulated by vitamin D. (2018)
  • Author(s): Nakamichi Yuko、Udagawa Nobuyuki、Suda Tatsuo、Takahashi Naoyuki
  • Journal Title: J Steroid Biochem Mol Biol Volume: 177 Pages: 70-76
  • DOI: 10.1016/j.jsbmb.2017.11.005
  • Peer Reviewed / Open Access
• [Journal Article] Chapter 18 Osteoclastogenesis and Vitamin D (2018)
  • Author(s): Nakamichi Y, Takahashi N, Udagawa N, Suda T
  • Journal Title: Vitamin D (Fourth Edition) Volume: 1 Pages: 309-317
  • DOI: 10.1016/b978-0-12-809965-0.00018-5
  • Peer Reviewed
• [Journal Article] The W9 peptide directly stimulates osteoblast differentiation via RANKL signaling. (2017)
  • Author(s): Nakamura M, Nakamichi Y, Mizoguchi T, Koide M, Yamashita T, Ara T, Nakamura H, Penninger JM, Furuya Y, Yasuda H, and Udagawa N
  • Journal Title: Journal of Oral Biosciences Volume: 59 Pages: 146-151
  • DOI: 10.1016/j.job.2017.05.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] VDR in osteoblast-lineage cells primarily mediates vitamin D treatment-induced increase in bone mass by suppressing bone resorption (2017)
  • Author(s): Nakamichi Y, Udagawa N, Horibe K, Mizoguchi T, Yamamoto Y, Nakamura T, Hosoya A, Kato S, Suda T, Takahashi N
  • Journal Title: Journal of Bone and Mineral Research Volume: 32 Pages: 1297-1308
  • DOI: 10.1002/jbmr.3096
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Roles of VDR in osteoblasts and osteoclasts for vitamin D-induced increase in bone mass: (2017)
  • Author(s): Nakamichi Y
  • Organizer: Bone Biology Forum (第14回)
  • Int'l Joint Research / Invited
• [Presentation] 骨ミネラル代謝における骨芽細胞および骨細胞の VDR の役割 (2017)
  • Author(s): 中道裕子
  • Organizer: Neo Vitamin D Workshop (第３回)
• [Presentation] 骨ミネラル代謝における骨芽細胞/骨細胞のVDRの役割 (2017)
  • Author(s): 中道裕子
  • Organizer: 25(OH)Dを考える会 (第４回)
  • Invited