Maintenance of bone homeostasis by DLL1-mediated Notch activation

• Project/Area Number: 26430094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Tokai University
• Principal Investigator: NAKAYAMA-MUGURUMA YUKARI 東海大学, 医学部, 助教 (80398750)
• Co-Investigator(Kenkyū-buntansha): 八幡 崇 東海大学, 医学部, 准教授 (10398753) ; 安藤 潔 東海大学, 医学部, 教授 (70176014)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Notchシグナル / 骨代謝 / 骨芽細胞 / リガンド特異性 / Notch / Jagged1 / Delta-like1 / リモデリング / Delta-like 1

Outline of Final Research Achievements

By using a transgenic approach that modified the expression of delta-like 1 (DLL-1) or Jagged1 in osteoblast-specific manner, we investigated the ligand-specific effects of Notch signaling in bone homeostasis. We demonstrated that the proper regulation of DLL1 expression in osteoblasts was essential for maintenance of bone remodeling. DLL1-Notch signaling promoted proliferation of committed but immature osteoblasts, thus being responsible for the expansion of bone forming cell pool. However, DLL1-Notch signaling inhibited further differentiation of those expanded osteoblasts to become fully mature functional osteoblasts, causing a substantial decrease in bone formation. Although osteoblast-specific expression of DLL1 did not alter intrinsic ability of osteoclasts, deregulation of osteoblast differentiation and maturation impaired maturation and function of osteoclasts due to a failed osteoblast-osteoclast coupling, resulting in severely suppressed bone metabolic turn-over.

Research Products

• [Journal Article] Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling. (2017)
  • Author(s): Muguruma Y, Hozumi K, Warita H, Yahata T, Uno T, Ito M, Ando K.
  • Journal Title: J Cell Physiol. Volume: 印刷中 Issue: 9 Pages: 2569-2580
  • DOI: 10.1002/jcp.25647
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Establishment of a humanized APL model via the transplantation of PML-RARA-transduced human common myeloid progenitors into immunodeficient mice (2014)
  • Author(s): Matsushita, H. Yahata, T. Sheng, Y. Nakamura, Y. Muguruma, Y. Matsuzawa, H. Tanaka, M. Hayashi, H. Sato, T. Damdinsuren, A. Onizuka, M. Ito, M. Miyachi, H. Pandolfi, P. P. Ando, K.
  • Journal Title: PLoS One Volume: 9 Issue: 11 Pages: e111082-e111082
  • DOI: 10.1371/journal.pone.0111082
  • Peer Reviewed / Open Access
• [Presentation] Jagged1-Notch interaction in the niche is responsible for acquisition of drug-resistance (2016)
  • Author(s): Muguruma Y, Hozumi K, Warita H, Yahata T, Uno T, Ito M, Ando K
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-14
• [Presentation] Intracellular PAI1 is a critical regulator of stem cell localization in the niche (2016)
  • Author(s): Takashi Yahata, Abd Aziz Ibrahim, Yukari Muguruma, Toshio Miyata, Kiyosi Ando
  • Organizer: Gordon Conference
  • Place of Presentation: Four Points Sheraton (CA, USA)
  • Year and Date: 2016-02-14
  • Int'l Joint Research
• [Presentation] Identification of molecular interactions in MM nich in vivo (2015)
  • Author(s): Yukari Muguruma, Takashi Yahata, Takayuki Warita, Yoshihiko Nakamura, Rikio Suzuki, Shumpei Ishikawa, Takayuki Isagawa,Kiyoshi Ando
  • Organizer: 日本血液学会
  • Place of Presentation: ホテル日航金沢(石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] In Vivo Analysis of PML-RARA in a Humanized Mouse Model (2014)
  • Author(s): Hiromichi Matsushita, Takashi Yahata,, Yin Sheng, Yoshihiko Nakamura, Yukari Muguruma, Hideyuki Matsuzawa, Masayuki Tanaka, Hideki Hayashi, Tadayuki Sato, Anar Damdinsuren, Makoto Onizuka, Mamoru Ito, Hayato Miyachi,, Pier Paolo Pandolfi, Kiyoshi Ando
  • Organizer: America Society of Hematology
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Jagged1-Notch signal supports human myeloma cell survival (2014)
  • Author(s): Yukari Muguruma, Takashi Yahata, Mamoru Itoh, Katsuto Hozumi, Mika Yamaguchi, Kiyoshi Ando
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02