Elucidation of osteoblast mineralization mechanism using McCunealbright syndrome iPS cells

• Project/Area Number: 18H03007
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Tokyo Dental College
• Principal Investigator: AZUMA TOSHIFUMI 東京歯科大学, 歯学部, 教授 (00222612)
• Co-Investigator(Kenkyū-buntansha): 中村 貴 東京歯科大学, 歯学部, 講師 (80431948) ; 柴原 孝彦 東京歯科大学, 歯学部, 教授 (50178919) ; 齋藤 淳 東京歯科大学, 歯学部, 教授 (60266559) ; 小野寺 晶子 東京歯科大学, 歯学部, 講師 (90637662) ; 齋藤 暁子 東京歯科大学, 歯学部, 助教 (90722835)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2020: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: GNAS / ヘッジホッグ / iPS細胞 / 骨芽細胞 / 骨 / 線維性骨異形成症 / McCune Albright 症候群 / 消化管腫瘍 / GPCR / Gorlin症候群 / McCuneAlbright症候群 / Hedgehog経路 / 骨代謝 / 骨粗しょう症治療薬 / cAMP / Hedgehog / iPS / 石灰化 / ｃAMP / マキューンオルブライト症候群 / ヘッジホッグ経路 / GANS / McCune Albright Syndrome

Outline of Final Research Achievements

The pathophysiology of congenital skeletal diseases is diverse, and it has been clarified that disease-specific iPS cell application is important for elucidating the pathophysiological mechanism of the disease. GNAS-rich iPS cells (fibrous dysplasia and McCune-Albright syndrome) iPS cells were generated and compared with Gorlin syndrome ipS cells, with the aim of elucidating the relationship and pathophysiology of the Hedgehog pathway and the GNAS pathway. When GNAS-rich iPS cells were established and neoplastic lesions were reproduced, it was found that the undifferentiated state of diseased cells was enhanced. Therefore, it was clarified that the inhibition of osteoblast differentiation in fibrous dysplasia may be directly linked to the treatment by appropriately correcting the inhibition of Hedgehog by drug administration.

Academic Significance and Societal Importance of the Research Achievements

GNAS過剰変異は　Sporadicに発生するMcCuneAlbright syndrome や　Fibrous dysplasia など　にみられる遺伝子変異であるが　その解明においては　上記疾患細胞の獲得が非常に困難であることが　大きな障害となっていた。　本研究にて　iPS細胞を作製したことにより　この疾患に関連した多くの疾患（線維性骨異形成症、消化管良性腫瘍　膵癌）の研究など広範に利用可能である、

Research Products

• [Journal Article] Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research (2020)
  • Author(s): Onodera Shoko、Nakamura Yuriko、Azuma Toshifumi
  • Journal Title: Int J Mol Sci. Volume: 21 Pages: 7559-7559
  • DOI: 10.3390/ijms21207559
  • Peer Reviewed / Open Access
• [Journal Article] A novel GNAS-mutated human induced pluripotent stem cell model for understanding GNAS-mutated tumors. (2020)
  • Author(s): Watanabe K, Nakamura T, Onodera S, Saito A, Shibahara T, Azuma T.
  • Journal Title: Tumour Biol. Volume: 42(9) Pages: 1177-1177
  • DOI: 10.1177/1010428320962588
  • Peer Reviewed
• [Journal Article] Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation (2020)
  • Author(s): Morita Nana、Onodera Shoko、Nakamura Yuriko、Nakamura Takashi、Takahashi Shin-ichi、Nomura Takeshi、Azuma Toshifumi
  • Journal Title: Med Mol Morphol. Volume: - Pages: 795-795
  • DOI: 10.1007/s00795-020-00264-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CAGE-seq analysis of osteoblast derived from cleidocranial dysplasia human induced pluripotent stem cells (2020)
  • Author(s): Ooki Akio、Onodera Shoko、Saito Akiko、Oguchi Akiko、Murakawa Yasuhiro、Sakamoto Teruo、Sueishi Kenji、Nishii Yasushi、Azuma Toshifumi
  • Journal Title: Bone Volume: 141 Pages: 115582-115582
  • DOI: 10.1016/j.bone.2020.115582
  • Peer Reviewed
• [Journal Article] The effects of parathyroid hormone on osteoblastic differentiation of mouse induced pluripotent stem cells in a 3-D culture model. (2020)
  • Author(s): Sato M, Aoki H, Nakamura T, Onodera S, Yamaguchi A, Saito A, Azuma T
  • Journal Title: .J Periodontal Res. Volume: 55 Pages: 734-743
  • DOI: 10.1111/jre.12762
  • Peer Reviewed
• [Journal Article] TSLP is a negative regulator of RANKL-induced osteoclastogenesis. (2020)
  • Author(s): Ohno, T., Nakamura, T., Nakae, S., Morita, H., Matsumoto, K., Takeda, K., Okumura, K., and Azuma, T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 530 Pages: 508-512
  • DOI: 10.1016/j.bbrc.2020.05.055
  • Peer Reviewed
• [Journal Article] Hedgehog Activation Regulates Human Osteoblastogenesis (2020)
  • Author(s): Onodera Shoko、Saito Akiko、Hojo Hironori、Nakamura Takashi、Zujur Denise、Watanabe Katsuhito、Morita Nana、Hasegawa Daigo、Masaki Hideki、Nakauchi Hiromitsu、Nomura Takeshi、Shibahara Takahiko、Yamaguchi Akira、Chung Ung-il、Azuma Toshifumi、Ohba Shinsuke
  • Journal Title: Stem Cell Reports. Volume: 15 Pages: 125-139
  • DOI: 10.1016/j.stemcr.2020.05.008
  • Peer Reviewed / Open Access
• [Journal Article] Tissue-nonspecific alkaline phosphatase promotes the osteogenic differentiation (2020)
  • Author(s): Nakamura T, Nakamura-Takahashi A, Kasahara M, Yamaguchi A, Azuma T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 524(3) Pages: 702-709
  • DOI: 10.1016/j.bbrc.2020.01.136
  • Peer Reviewed / Open Access
• [Journal Article] Stage-dependent differential gene expression profiles of cranial neural (2020)
  • Author(s): Odashima A, Onodera S, Saito A, Ogihara Y, Ichinohe T, Azuma T.
  • Journal Title: Med Mol Morphol. Volume: 53(1) Pages: 1007-1007
  • DOI: 10.1007/s00795-019-00229-2
  • Peer Reviewed / Open Access
• [Journal Article] Stepwise strategy for generating osteoblasts from human pluripotent stem cells under fully defined xeno-free conditions with small-molecule inducers (2020)
  • Author(s): Zujur Denise、Kanke Kosuke、Onodera Shoko、Tani Shoichiro、Lai Jenny、Azuma Toshifumi、Xin Xiaonan、Lichtler Alexander C.、Rowe David W.、Saito Taku、Tanaka Sakae、Masaki Hideki、Nakauchi Hiromitsu、Chung Ung-il、Hojo Hironori、Ohba Shinsuke
  • Journal Title: Regen Ther Volume: 14 Pages: 19-31
  • DOI: 10.1016/j.reth.2019.12.010
  • Peer Reviewed / Open Access / Int'l Joint Research