Development of a new experimental model for fibrodysplasia ossificans progressiva

• Project/Area Number: 15K15556
• 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): 2015-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 希少疾患 / 異所性骨化 / 病態モデル / ES細胞 / BMP

Outline of Final Research Achievements

Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as skeletal muscle, tendon and ligament. ALK2 was identified as a molecule responsible for FOP, and an R206H mutation of ALK2 was found in patients with typical FOP. Recently, we established mouse ES cell lines, which express human ALK2(R206H) under the control of Tet-Off system. In the present study, we analyzed karyotypes of the ES cell lines and found that they had a translocation, duplication and an addition of a fragment of chromosomes. In the absence of Dox, they differentiated to chondrocytes in vitro in response to a stimulation by the TGF- β family ligand. These results suggest that the ES cell lines are novel model systems for FOP, at least in in vitro.

Research Products

• [Journal Article] A door opens for fibrodysplasia ossificans progressiva. (2016)
  • Author(s): Katagiri T.
  • Journal Title: Trends in Biochemical Sciences Volume: 41 Issue: 2 Pages: 119-121
  • DOI: 10.1016/j.tibs.2015.11.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 進行性骨化性線維異形成症（FOP）と骨免疫学 (2016)
  • Author(s): 片桐岳信
  • Journal Title: Clinical Calcium Volume: 26 Pages: 691-698
  • Acknowledgement Compliant
• [Presentation] A role of FKBP12 in signal transduction of mutant ALK2 responsible for fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. (2016)
  • Author(s): Machiya A, Fujimoto M, Ohte S, Tsukamoto S, Osawa K, Kuratani M, Bullock AN, Suda N, Katagiri T
  • Organizer: BMP Signaling in Cancer
  • Place of Presentation: St. Catharine's College (ケンブリッジ、イギリス）
  • Year and Date: 2016-03-15
  • Int'l Joint Research
• [Presentation] TGF-β signaling suppresses chondrocyte differentiation. (2016)
  • Author(s): Tsukamoto S, Ohte S, Sekine N, Kuratani M, Machiya A, Katagiri T.
  • Organizer: Gordon Research Conference on Bones & Teeth.
  • Place of Presentation: Hotel Galves （ガルベストン、テキサス州、アメリカ）
  • Year and Date: 2016-02-17
  • Int'l Joint Research
• [Presentation] Establishment and characterization of Tet-On C2C12 cell lines that express mutant ALK2 responsible for fibrodysplasia ossificans progressiva. (2016)
  • Author(s): Katagiri T, Ohte Tsukamoto S, Yoneyama K, Kuratani M, Machiya A.
  • Organizer: Gordon Research Conference on Bones & Teeth.
  • Place of Presentation: Hotel Galves （ガルベストン、テキサス州、アメリカ）
  • Year and Date: 2016-02-15
  • Int'l Joint Research
• [Presentation] 骨格筋組織における異所性骨形成 (2015)
  • Author(s): 片桐岳信
  • Organizer: 九州大学口腔細胞工学セミナー
  • Place of Presentation: 九州大学（福岡県福岡市）
  • Year and Date: 2015-12-09
  • Invited
• [Presentation] 進行性骨化性線維異形成症（FOP）における筋損傷後の骨化の誘発 (2015)
  • Author(s): 倉谷麻衣、町谷亜位子、藤本舞、大澤賢次、塚本翔、大手聡、片桐岳信
  • Organizer: 精神・神経疾患研究開発費「筋ジストロフィーモデル動物を用いた新たな治療法の開発」班班会議
  • Place of Presentation: 国立精神・神経医療研究センター 神経研究所教育研究棟ユニバーサルホール（東京都小平市）
  • Year and Date: 2015-12-08
  • Invited
• [Presentation] 進行性骨化性線維異形成症における変異ALK2の活性化機序. (2015)
  • Author(s): 倉谷麻衣、町谷亜位子、藤本舞、塚本翔、大手聡、片桐岳信.
  • Organizer: 第3回若手による骨格筋細胞研究会
  • Place of Presentation: 九州大学（福岡県福岡市）
  • Year and Date: 2015-11-24
• [Presentation] 進行性骨化性線維異形成症におけるFKBP12の役割. (2015)
  • Author(s): 町谷亜位子、藤本舞、須田直人、片桐岳信.
  • Organizer: 第74回日本矯正歯科学会大会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-18
• [Presentation] Establishment and characterization of C2C12 cells expressing human ALK2 under control of Tet-On system. (2015)
  • Author(s): Ohte S, Yoneyama K, Tsukamoto S, Kuratani M, MacHiya A, Katagiri T.
  • Organizer: Australian New Zealand Bone & Mineral Society (ANZBMS) Annual Meeting 2015
  • Place of Presentation: Hotel Grand Chancellor (Hobart, Tasmania, Australia)
  • Year and Date: 2015-11-01
  • Int'l Joint Research
• [Presentation] A role of FKBP12 in activation of mutant ALK2 responsible for fibrodysplasia ossificans progressiva (FOP). (2015)
  • Author(s): Machiya A, Fujimoto M, Ohte S, Tsukamoto S, Suda N, Katagiri T.
  • Organizer: Australian New Zealand Bone & Mineral Society (ANZBMS) Annual Meeting 2015
  • Place of Presentation: Hotel Grand Chancellor (Hobart, Tasmania, Australia)
  • Year and Date: 2015-11-01
  • Int'l Joint Research
• [Presentation] TGF-βファミリーによる運動器の制御 (2015)
  • Author(s): 片桐岳信
  • Organizer: 第13回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉医科大学創立30周年記念講堂(埼玉県日高市)
  • Year and Date: 2015-10-31
  • Invited
• [Presentation] 進行性骨化性線維異形成症（FOP）の骨化シグナル活性化機構におけるFKBP12とII型BMP受容体の役割. (2015)
  • Author(s): 町谷亜位子、藤本舞、大手聡、塚本翔、倉谷麻衣、須田直人、片桐岳信.
  • Organizer: 第13回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉医科大学創立30周年記念講堂(埼玉県日高市)
  • Year and Date: 2015-10-30
• [Presentation] Role of FKBP12 in signal transduction by mutant ALK2 responsible for fibrodysplasia ossificans progressiva. (2015)
  • Author(s): Machiya A, Fujimoto M, Tsukamoto S, Kuratani M, Ohte S, Suda N, Katagiri T.
  • Organizer: American Society for Bone and Mineral Research (ASBMR) 2015 Annual Meeting
  • Place of Presentation: Seattle Convention Center (Seattle, Washington, USA)
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] 進行性骨化性線維異形成症（FOP）のALK2変異体の活性化機構におけるFKBP12とBMP II型受容体の役割. (2015)
  • Author(s): 町谷亜位子、藤本舞、須田直人、片桐岳信.
  • Organizer: 第57回歯科基礎医学会学術大会
  • Place of Presentation: 朱鷺メッセ（新潟県新潟市）
  • Year and Date: 2015-09-12
• [Presentation] FOPの最前線 (2015)
  • Author(s): 片桐岳信
  • Organizer: J-FOP患者家族会交流会 特別講演
  • Place of Presentation: ホテルグランドヒル市ヶ谷(東京都新宿区)
  • Year and Date: 2015-09-05
  • Invited
• [Presentation] 生理的および病的骨形成のメカニズム (2015)
  • Author(s): 片桐岳信
  • Organizer: 第33回日本骨代謝学会学術集会 Meet the Expert 6
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-25
  • Invited
• [Presentation] BMPと骨形成 (2015)
  • Author(s): 片桐岳信
  • Organizer: 第33回日本骨代謝学会学術集会 学術賞受賞講演
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-24
  • Invited
• [Presentation] 進行性骨化性線維異形成症（FOP）のALK2変異体活性化におけるFKBP12の役割. (2015)
  • Author(s): 町谷亜位子、藤本舞、塚本翔、大澤賢次、大手聡、須田直人、片桐岳信.
  • Organizer: 第33回日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-23
• [Presentation] Establishment of a novel model of heterotopic ossification in skeletal muscle in fibrodysplasia ossificans progressiva. (2015)
  • Author(s): Katagiri T, Tsukamoto S, Ohte S, Machiya A, Kuratani M.
  • Organizer: Gordon Research Conference on Myogenesis.
  • Place of Presentation: Renaissance Tuscany Il Ciocco (Lucca, Italy)
  • Year and Date: 2015-06-21
  • Int'l Joint Research
• [Presentation] Recent topics on fibrodysplasia ossificans progressiva. (2015)
  • Author(s): Katagiri T
  • Organizer: Seminar (Sapienza University of Rome)
  • Place of Presentation: Sapienza University of Rome
  • Year and Date: 2015-06-19
  • Int'l Joint Research / Invited
• [Book] Novel in vitro models to study osteogenesis and chondrogenesis for human skeletal disorders .In Bone Morphogenetic Proteins: Systems Biology Regulators. Sampath TK and Vukicevic S, editors. (2016)
  • Author(s): Katagiri T
  • Total Pages: 20
  • Publisher: Springer, London
• [Book] Bone Morphogenetic Proteins. In The TGF-β Family. Miyazono K and Derynck R, editors. (2016)
  • Author(s): Katagiri T and Watabe T
  • Total Pages: 30
  • Publisher: Cold Spring Harbor Press, New York
• [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, Zreiqat H, Rosen V and Dunstan C, editors. (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
  • URL: http://www.saitama-med.ac.jp/genome/