Elucidation of the involvement of hedgehog-Gli1 axis in the bone remodeling by tooth movement.

• Project/Area Number: 17K11932
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthodontics/Pediatric dentistry
• Research Institution: The University of Tokyo
• Principal Investigator: Ohkubo Kazumi 東京大学, 医学部附属病院, 講師 (10396715)
• Co-Investigator(Kenkyū-buntansha): 岡安 麻里 東京大学, 医学部附属病院, 病院診療医(出向) (10610941) ; 大庭 伸介 大阪大学, 大学院歯学研究科, 教授 (20466733) ; 西條 英人 東京大学, 医学部附属病院, 准教授 (80372390)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 歯科矯正学 / ヘッジホッグ-Gli1 / 歯科矯正 / ヘッジホッグシグナル

Outline of Final Research Achievements

In this study, to clarify the involvement of Hedgehog-Gli1 axis in the regulation of bone metabolism in maxillofacial bone, we conducted an integrative study using mouse genetics and genome-wide analysis. First, micro-CT analysis in adult Gli1-KO mice revealed impaired craniofacial bone formation in Gli1-KO mice compared to wild-type mice. In vitro analysis using bone marrow-derived stromal cells confirmed the suppression of the osteoblast differentiation by Gli1-KO. A comprehensive genome-wide analysis revealed Gli1-mediated transcriptional regulatory regions and Gli1’s functional target genes. These results suggest that those Gli1’s downstream factors are involved in bone remodeling.

Academic Significance and Societal Importance of the Research Achievements

成体の骨組織は、骨基質の吸収と形成というダイナミックな現象（骨改造現象－骨リモデリング）により常に再構築され、その形態と機能のホメオスタシスを維持している。本研究では、遺伝子改変技術とゲノムワイド解析を駆使することで、ヘッジホッグ-Gli1経路の骨形成に対する作用を網羅的に研究した。ヘッジホッグシグナルは骨形成と骨吸収を司る重要なシグナル因子であるため、本研究成果は、顎顔面骨の骨代謝調節の基礎的な知見となるだけでなく、将来的に歯科矯正治療へ寄与する可能性を秘めている。

Research Products

• [Journal Article] Single-cell RNA sequencing unravels heterogeneity of skeletal progenitors and cell-cell interactions underlying the bone repair process (2022)
  • Author(s): Nakayama Mika、Okada Hiroyuki、Seki Masahide、Suzuki Yutaka、Chung Ung-il、Ohba Shinsuke、Hojo Hironori
  • Journal Title: Regenerative Therapy Volume: 21 Pages: 9-18
  • DOI: 10.1016/j.reth.2022.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages (2022)
  • Author(s): Hojo Hironori, Saito Taku, He Xinjun, Guo Qiuyu, Onodera Shoko, Azuma Toshifumi, Koebis Michinori, Nakao Kazuki, Aiba Atsu, Seki Masahide, Suzuki Yutaka, Okada Hiroyuki, Tanaka Sakae, Chung Ung-il, McMahon Andrew P., Ohba Shinsuke
  • Journal Title: Cell Reports Volume: 40 Issue: 10 Pages: 111315-111315
  • DOI: 10.1016/j.celrep.2022.111315
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Orally administrable peptides derived from egg yolk promote skeletal repair and ameliorate degenerative skeletal disorders in mouse models (2022)
  • Author(s): Kitaura Yoshiaki、Nakamura Utano、Awada Chihiro、Yamaguchi Motonori、Kim Mujo、Ikeda Yuki、Matsuo Yuki、Moriishi Takeshi、Sawase Takashi、Chung Ung-il、Hojo Hironori、Ohba Shinsuke
  • Journal Title: Regenerative Therapy Volume: 21 Pages: 584-595
  • DOI: 10.1016/j.reth.2022.11.002
  • Peer Reviewed / Open Access
• [Journal Article] Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin (2021)
  • Author(s): Wang JS, Kamath T, Mazur CM, Mirzamohammadi F, Rotter D, Hojo H, Castro CD, Tokavanich N, Patel R, Govea N, Enishi T, Wu Y, da Silva Martins J, Bruce M, Brooks DJ, Bouxsein ML, Tokarz D, Lin CP, Abdul A, Macosko EZ, Fiscaletti M, Munns CF, Ryder P, Kost-Alimova M, Byrne P, Cimini B, Fujiwara M, Kronenberg HM, Wein MN.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 6271-6271
  • DOI: 10.1038/s41467-021-26571-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mesenchymal stromal cells in the bone marrow niche consist of multi-populations with distinct transcriptional and epigenetic properties (2021)
  • Author(s): Kanazawa Sanshiro、Okada Hiroyuki、Hojo Hironori、Ohba Shinsuke、Iwata Junichi、Komura Makoto、Hikita Atsuhiko、Hoshi Kazuto
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 15811-15811
  • DOI: 10.1038/s41598-021-94186-5
  • Peer Reviewed / Open Access
• [Journal Article] Gene regulatory landscape in osteoblast differentiation (2020)
  • Author(s): Hojo Hironori、Ohba Shinsuke
  • Journal Title: Bone Volume: 137 Pages: 115458-115458
  • DOI: 10.1016/j.bone.2020.115458
  • NAID: 120006988169
  • Peer Reviewed
• [Journal Article] Understanding paraxial mesoderm development and sclerotome specification for skeletal repair (2020)
  • Author(s): Tani Shoichiro、Chung Ung-il、Ohba Shinsuke、Hojo Hironori
  • Journal Title: Experimental & Molecular Medicine Volume: 52 Issue: 8 Pages: 1166-1177
  • DOI: 10.1038/s12276-020-0482-1
  • Peer Reviewed / Open Access
• [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 Issue: 1 Pages: 125-139
  • DOI: 10.1016/j.stemcr.2020.05.008
  • Peer Reviewed / Open Access
• [Journal Article] Influence of Damage-Associated Molecular Patterns from Chondrocytes in Tissue-Engineered Cartilage (2020)
  • Author(s): Fujihara Yuko、Abe Takahiro、Asawa Yukiyo、Nishizawa Satoru、Saijo Hideto、Hikita Atsuhiko、Hoshi Kazuto
  • Journal Title: Tissue Engineering Part A Volume: 00 Issue: 1-2 Pages: 1-9
  • DOI: 10.1089/ten.tea.2019.0185
  • 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: 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] A Comparative Study of Oral Health Status between International and Japanese University Student Patients in Japan (2018)
  • Author(s): Ohsato Ai、Abe Masanobu、Ohkubo Kazumi、Yoshimasu Hidemi、Zong Liang、Hoshi Kazuto、Takato Tsuyoshi、Yanagimoto Shintaro、Yamamoto Kazuhiko
  • Journal Title: Healthcare Volume: 6 Issue: 2 Pages: 52-52
  • DOI: 10.3390/healthcare6020052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of cleft lip and palate associated with unilateral choanal atresia (2018)
  • Author(s): Fujihara Yuko、Kikuta Shu、Sugiyama Madoka、Kubota Keigo、Ishibashi Makiko、Igarashi Masaki、Saijo Hideto、Hoshi Kazuto
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 30 Issue: 6 Pages: 538-541
  • DOI: 10.1016/j.ajoms.2018.06.007
  • Peer Reviewed
• [Journal Article] Clinical Findings of a Cantilever Iliac Bone Graft for Secondary Correction of Cleft Lip-Nose Deformities (2018)
  • Author(s): Sugiyama M, Nakatsuka T, Saijo H, Fujihara Y, Kanno Y, Hikita A, Takato T, Hoshi K
  • Journal Title: J Craniofac Surg Volume: 掲載確定 Issue: 3 Pages: 741-746
  • DOI: 10.1097/scs.0000000000004070
  • Peer Reviewed
• [Journal Article] Improving chondrocyte hargests with poly(2-hydroxyethyl methacrylate) coated materials in the preparation for cartilage tissue engineering (2017)
  • Author(s): Harata M, Watanabe M, Nagata S, Ko EC, Ohba S, Takato T, Hikita A, Hoshi K
  • Journal Title: Regenerative Therapy Volume: 7 Pages: 61-71
  • DOI: 10.1016/j.reth.2017.08.002
  • Peer Reviewed / Open Access
• [Presentation] Understanding mechanisms underlying cell fate specification of dental mesenchymal cells in the developing tooth germ through single-cell transcriptome (2022)
  • Author(s): Dahlia Eldeeb, Hironori Hojo, Hiroyuki Okada, Yutaka Suzuki, Masahide Seki, Junichi Tanaka, Shinsuke Ohba, Ung-il Chung
  • Organizer: MBSJ 2022
• [Presentation] Understanding a mechanism underlying bone repair process and application for bone regeneration (2021)
  • Author(s): Hironori Hojo
  • Organizer: SICEM 2021
  • Int'l Joint Research / Invited
• [Presentation] Runx2 defines the osteoblast chromatin landscape in skeletal development (2020)
  • Author(s): Hojo H, Saito T, Onodera S, Azuma T, Chung UI, Seki M, Suzuki Y, McMahon AP, Ohba S
  • Organizer: American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Runx2は骨格発生においてクロマチンランドスケープを規定する (2020)
  • Author(s): 北條宏徳、齋藤琢、小野寺晶子、東俊文、鄭雄一、大庭伸介
  • Organizer: 第38回日本骨代謝学会
• [Presentation] Exploring the gene regulatory landscape in skeletal cells (2019)
  • Author(s): Ohba S
  • Organizer: 2019 Gordon Research Conference Cartilage Biology & Pathology
  • Int'l Joint Research / Invited
• [Presentation] A system level investigation to unravel mechanisms and potential direct targets of the osteogenige small molecule TH (2017)
  • Author(s): Ichsan M, Kanke K, Hojo H, Chung UI, Ohba S
  • Organizer: EMBL Conference: Mamalian Genetics and Genomics: From Molecular Mechanisms to Translational Applications
  • Int'l Joint Research