Novel regulators of bone-inducing activity of BMP

• Project/Area Number: 25670658
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Saitama Medical University
• Principal Investigator: KATAGIRI Takenobu 埼玉医科大学, 医学部, 教授 (80245802)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: BMP / Smad / 分化 / シグナル伝達 / 転写 / 蛋白質 / 細胞内情報伝達 / 骨 / リン酸化 / 転写制御

Outline of Final Research Achievements

Bone morphogenetic proteins (BMPs) are growth factors, which play crucial role for bone formation during embryonic development and tissue regeneration. Intracellular signaling of BMPs is induced by transmembrane serine/threonine kinase receptors to nuclei via phosphorylation reactions. Smad, MAPK and PI3K pathways have been shown to be activated by the BMP receptors. We examined the role of Smad1, Smad5, and Smad9 by creating constitutively active forms (SmadDXD). Transcriptional activity of Smad9DVD was lower than that of Smad1DXD or Smad5DXD. The linker region of Smad9 was distinguished from those of Smad1 and Smad5 and sufficient to reduce transcriptional activity. The unique structure of Smad9 linker region seemed to recruit corepressors to the target DNA. These findings suggest that BMP receptors phosphorylate signaling molecules, which regulate positively and negatively transcription of a target gene.

Research Products

• [Journal Article] Bone morphogenetic protein-induced heterotopic bone formation: What have we learned from the history of a half century? (2015)
  • Author(s): Katagiri T, Osawa K, Tsukamoto, Fujimoto M, Miyamoto A, Mizuta T.
  • Journal Title: Jpn Dent Sci Rev Volume: 51 Issue: 2 Pages: 42-50
  • DOI: 10.1016/j.jdsr.2014.09.004
  • NAID: 50009645833
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smad9 is a new type of transcriptional regulator in bone morphogenetic protein signaling. (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Machiya A, Jimi E, Kokabu S, Katagiri T.
  • Journal Title: Scientific Reports Volume: 4 Issue: 1 Pages: 7596-7596
  • DOI: 10.1038/srep07596
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of TLE3 by bone marrow stromal cells is regulated by canonical Wnt signaling (2014)
  • Author(s): Kokabu S, Sato T, Ohte S, Enoki Y, Okubo M, Katagiri T, Rosen V, Yoda T.
  • Journal Title: Federation of European Biochemical Societies letters Volume: 588 Issue: 4 Pages: 614-619
  • DOI: 10.1016/j.febslet.2013.12.031
  • Peer Reviewed
• [Journal Article] TGF-βファミリーから見える骨と筋の新しい接点. (2014)
  • Author(s): 片桐岳信、塚本翔、大澤賢次
  • Journal Title: 実験医学別冊 Volume: 32 Pages: 1010-1016
• [Journal Article] The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway (2013)
  • Author(s): Katagiri T, Tsukamoto S.
  • Journal Title: Biological Chemistry Volume: 394 Issue: 6 Pages: 703-714
  • DOI: 10.1515/hsz-2012-0310
  • Peer Reviewed
• [Journal Article] TLE3, transducing-like enhancer of split 3, suppresses osteoblast differentiation of bone marrow stromal cells (2013)
  • Author(s): Kokabu S, Nguyen T, Ohte S, Sato T, Katagiri T, Yoda T, Rosen V.
  • Journal Title: Biochemical and biophysical research communications Volume: 438 Issue: 1 Pages: 205-210
  • DOI: 10.1016/j.bbrc.2013.07.054
  • Peer Reviewed
• [Journal Article] 進行性骨化性線維異形成症（FOP） (2013)
  • Author(s): 片桐岳信
  • Journal Title: Bone Joint Nerve Volume: 3 Pages: 53-60
• [Presentation] Musculoskeletal system and the TGF-β family (2014)
  • Author(s): Katagiri T
  • Organizer: 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉県日高市、埼玉医科大学創立30周年記念講堂
  • Year and Date: 2014-11-01
  • Invited
• [Presentation] Smad9 is a new type of transcriptional repressor in BMP signaling (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 埼玉県日高市、埼玉医科大学創立30周年記念講堂
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Smad8はBMPシグナルの新しいタイプの制御因子である (2014)
  • Author(s): 片桐岳信、藤本舞、大澤賢次、自見英治郎、古株彰一郎
  • Organizer: 第56回歯科基礎医学会学術大会・総会
  • Place of Presentation: 福岡県福岡市、福岡国際会議場
  • Year and Date: 2014-09-27
• [Presentation] Establishment of a novel model of chondrogenesis using murine ES cells carrying mutant ALK2 and more... (2014)
  • Author(s): Katagiri T
  • Organizer: 10th International Conference on BMPs
  • Place of Presentation: ベルリン、ドイツ
  • Year and Date: 2014-09-19
  • Invited
• [Presentation] Smad8 is a novel regulator of BMP signaling (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: 10th International Conference on BMPs
  • Place of Presentation: ベルリン、ドイツ
  • Year and Date: 2014-09-19
• [Presentation] Smad8 negatively regulates BMP signaling in a dominant negative fashion (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: 2014 ASBMR Annual Meeting
  • Place of Presentation: ヒューストン、アメリカ
  • Year and Date: 2014-09-13
• [Presentation] Smad8による新たなBMPシグナルの制御機構 (2014)
  • Author(s): 塚本翔、水田誉人、藤本舞、大手聡、大澤賢次、宮本阿礼、米山克美、村田栄子、自見英治郎、古株彰一郎、片桐岳信
  • Organizer: 第21回BMP研究会
  • Place of Presentation: 大阪府大阪市、大阪大学中之島センター メモリアルホール
  • Year and Date: 2014-07-26
• [Presentation] A novel regulation of BMP signaling by Smad8 (2014)
  • Author(s): Tsukamoto S, Mizuta T, Fujimoto M, Ohte S, Osawa K, Miyamoto A, Yoneyama K, Murata E, Jimi E, Kokabu S, Katagiri T
  • Organizer: FASEB Science Research Conferences on Skeletal Muscle Satellite and Stem Cells
  • Place of Presentation: スティームボート・スプリングズ、アメリカ
  • Year and Date: 2014-07-20 – 2014-07-25
• [Presentation] Smad8はBMPシグナルを抑制的に調節する (2013)
  • Author(s): 片桐岳信、藤本舞、古株彰一郎、自見英治郎、大澤賢次
  • Organizer: 第55回歯科基礎医学会学術大会・総会
  • Place of Presentation: 岡山
• [Presentation] コリプレッサー TLE3 は HDAC を介して骨芽細 胞分化を抑制する. (2013)
  • Author(s): 古株彰一郎、佐藤毅、榎木祐一郎、大久保正彦、片桐岳信、依田哲也
  • Organizer: 第55回歯科基礎医学会学術大会・総会
  • Place of Presentation: 岡山
• [Presentation] Smad8 is a Novel Type Regulator of BMP Signaling. (2013)
  • Author(s): Sho Tsukamoto, Satoshi Ohte, Mai Fujimoto, Takato Mizuta, Arei Miyamoto, Kenji Osawa, Shoichiro Kokabu, Eiko Murata, Eijiro Jimi, Takenobu Katagiri
  • Organizer: 2013 ASBMR Symposium: Cutting Edge Discoveries in Muscle Biology, Disease and Therapeutics
  • Place of Presentation: ボルチモア、メリーランド州、アメリカ
  • Invited
• [Presentation] Smad8 is a Novel Type Regulator of BMP Signaling. (2013)
  • Author(s): Sho Tsukamoto, Satoshi Ohte, Mai Fujimoto, Takato Mizuta, Arei Miyamoto, Kenji Osawa, Shoichiro Kokabu, Eiko Murata, Eijiro Jimi, Takenobu Katagiri
  • Organizer: 2013 ASBMR Annual Meeting
  • Place of Presentation: ボルチモア、メリーランド州、アメリカ
• [Presentation] BMP3 Expression by Osteoblasts Is Regulated by Canonical Wnt Signaling. (2013)
  • Author(s): Shoichiro Kokabu, Laura Gamer, Jonathan Lowery, Tsuyoshi Sato, Tetsuya Yoda, Takenobu Katagiri, Vicki Rosen
  • Organizer: 2013 ASBMR Annual Meeting
  • Place of Presentation: ボルチモア、メリーランド州、アメリカ
• [Book] Ligand–Receptor Interactions and Their Implications in Delivering Certain Signaling for Bone Regeneration. In A Tissue Regeneration Approach to Bone and Cartilage Repair, Mechanical Engineering Series (2015)
  • Author(s): Katagiri T, Tsukamoto S, Osawa K, and Kokabu S
  • Total Pages: 15
  • Publisher: Springer, London
• [Remarks] 埼玉医科大学 ゲノム医学研究センター 病態生理部門
  • URL: http://www.saitama-med.ac.jp/genome/Div04_PPhysiol/index.html
• [Remarks] 埼玉医科大学ゲノム医学研究センター 病態生理部門
  • URL: http://www.saitama-med.ac.jp/genome/Div04_PPhysiol/index.html