Understanding of Runx2-mediated hierarichical gene regulatory network in bone formation and application of the network for bone regeneration

• Project/Area Number: 17H05106
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Surgical dentistry
• Research Institution: The University of Tokyo
• Principal Investigator: Hojo Hironori 東京大学, 大学院医学系研究科(医学部), 准教授 (80788422)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥24,440,000 (Direct Cost: ¥18,800,000、Indirect Cost: ¥5,640,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2017: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
• Keywords: 転写制御 / 骨発生 / Runx2 / エピゲノム / 転写因子 / 発生・分化 / 発現制御 / バイオインフォマティクス / 骨形成

Outline of Final Research Achievements

Runx2 is an essential transcription factor for both osteoblast specification and chondrocyte hypertrophy. In this study, we performed integrative analysis of Runx2-DNA binding profile and cell-type distinct epigenetic landscape profile in mouse neonatal osteoblasts and chondrocytes. We identified cell-type specific putative enhancers targeted by Runx2 in osteoblasts and chondrocytes, and confirmed a biological function of these. Through this study, we identified a Runx2-mediated gene regulatory program in skeletal development.

Academic Significance and Societal Importance of the Research Achievements

転写因子Runx2は骨を形成する骨芽細胞の分化決定・成熟化を促進する作用と、軟骨組織に存在する軟骨細胞の分化・肥大化を進める作用を有しており、これらのメカニズム解明は、骨格組織の再生医療法の確立や疾患の分子病態の理解に必須である。本研究では、Runx2の骨芽細胞と軟骨細胞に対する作用メカニズムの一端を、ゲノムワイドな転写制御機構の観点から明らかにし、骨格再生に向けた基礎的知見を取得した。

Research Products

• [Int'l Joint Research] 南カリフォルニア大学/マサチューセッツ総合病院/アメリカ国立衛生研究所(米国)
• [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: Regenerative Therapy Volume: 14 Pages: 19-31
  • DOI: 10.1016/j.reth.2019.12.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Insights into Gene Regulatory Networks in Chondrocytes (2019)
  • Author(s): Hojo Hironori、Ohba Shinsuke
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 24 Pages: 6324-6324
  • DOI: 10.3390/ijms20246324
  • Peer Reviewed / Open Access
• [Journal Article] Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone (2019)
  • Author(s): Xuan Fengjun、Yano Fumiko、Mori Daisuke、Chijimatsu Ryota、Maenohara Yuji、Nakamoto Hideki、Mori Yoshifumi、Makii Yuma、Oichi Takeshi、Taketo Makoto Mark、Hojo Hironori、Ohba Shinsuke、Chung Ung-il、Tanaka Sakae、Saito Taku
  • Journal Title: Arthritis Research & Therapy Volume: 21 Issue: 1 Pages: 247-247
  • DOI: 10.1186/s13075-019-2041-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simple and Robust Differentiation of Human Pluripotent Stem Cells toward Chondrocytes by Two Small-Molecule Compounds (2019)
  • Author(s): Kawata Manabu、Mori Daisuke、Kanke Kosuke、Hojo Hironori、Ohba Shinsuke、Chung Ung-il、Yano Fumiko、Masaki Hideki、Otsu Makoto、Nakauchi Hiromitsu、Tanaka Sakae、Saito Taku
  • Journal Title: Stem Cell Reports Volume: 13 Issue: 3 Pages: 530-544
  • DOI: 10.1016/j.stemcr.2019.07.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of orthotopically functional salivary gland from embryonic stem cells (2018)
  • Author(s): Tanaka Junichi、Ogawa Miho、Hojo Hironori、Kawashima Yusuke、Mabuchi Yo、Hata Kenji、Nakamura Shiro、Yasuhara Rika、Takamatsu Koki、Irie Tarou、Fukada Toshiyuki、Sakai Takayoshi、Inoue Tomio、Nishimura Riko、Ohara Osamu、Saito Ichiro、Ohba Shinsuke、Tsuji Takashi、Mishima Kenji
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4216-4216
  • DOI: 10.1038/s41467-018-06469-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of the gene-regulatory landscape in skeletal development and potential links to skeletal regeneration. (2017)
  • Author(s): Hojo H, Chung UI, Ohba S
  • Journal Title: Regenerative Therapy Volume: 6 Pages: 100-107
  • DOI: 10.1016/j.reth.2017.04.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Three-dimensional system enabling the maintenance and directed differentiation of pluripotent stem cells under defined conditions (2017)
  • Author(s): Zujur D, Kanke K, Lichtler AC, Hojo H, Chung UI, Ohba S
  • Journal Title: Science Advanvces Volume: 3 Issue: 5
  • DOI: 10.1126/sciadv.1602875
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Cell-type-distinct regulatory action of Runx2 on the genome underlies its distinct roles in osteoblasts and chondrocytes. (2019)
  • Author(s): Hojo H, Ohba S, Yamakawa A, Guo Q, He X, Saito T, Onodera S, Azuma T, Chung UI, McMahon AP.
  • Organizer: 2019 Annual Meeting of the American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] De novo missense mutation in SP7 in a patient with cranial hyperostosis, long bone fragility, and increased osteoblast number. (2019)
  • Author(s): Lui J, Raimann A, Dong L, Hojo H, Roschger P, Fratzl-Zelman N, Jee YH, Haeusler G, Baron J
  • Organizer: 2019 Annual Meeting of the American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] A Novel SP7/OSTN Axis Controls Osteocyte Morphology and Function (2019)
  • Author(s): Wang JS, Mirzamohammadi F, Hojo H, Rotter D, Castro Andrade CD, Fiscaletti M, Kronenberg HM, Wein MN
  • Organizer: 2019 Annual Meeting of the American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Runx2は骨格発生において細胞種特異的な転写制御領域に作用する (2019)
  • Author(s): 1.北條宏徳、山川晃、齋藤琢、小野寺晶子、東俊文、鄭雄一、大庭伸介
  • Organizer: 第37回日本骨代謝学会学術集会,
• [Presentation] Identification of a chondrocyte-specific Indian hedgehog enhancer and Sox9-mediated mechanisms of the enhancer activation (2018)
  • Author(s): Yamakawa A, Hojo H, Chung UI, Ohba S
  • Organizer: OARSI World Congress on Osteoarthritis
  • Int'l Joint Research
• [Presentation] Role of Osterix (SP7) in Regulating Osteocyte Biology and Dendrite Formation (2018)
  • Author(s): Mirzamohammadi F, Hojo H, Enishi T, Govea N, Kronenberg HM, Wein MN
  • Organizer: 2018 Annual Meeting of the American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Modeling of bone remodeling by three-dimensional co-culture of mouse embryonic stem cell-derived osteoblasts and osteoclast precursors (2017)
  • Author(s): Zujur DC, Hikita A, Kanke K, Hojo H, Chung UI, Ohba S
  • Organizer: International Society for Stem Cell Research 15th Annual Meeting
  • Int'l Joint Research
• [Presentation] In vivo bone formation by osteoblasts generated from human induced pluripotent stem cells under fully defined xeno-free conditions (2017)
  • Author(s): Zujur DC, Kanke K, Hojo H, Onodera S, Azuma T, Chung UI, Ohba S
  • Organizer: 39th Annual Meeting of the American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] A system level investigation to unravel mechanisms and potential direct targets of the osteogenic small molecule TH (2017)
  • Author(s): Ichsan M, Kanke K, Hojo H, Chung UI, Ohba S
  • Organizer: EMBL Conference: Mammalian Genetics and Genomics
  • Int'l Joint Research