Analysis of bone metabolism based on mutant ALK2 receptor assosiated with FOP.

• Project/Area Number: 25861339
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Saitama Medical University
• Principal Investigator: MIYAMOTO Arei 埼玉医科大学, 医学部, 研究員 (70634591)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 骨系統疾患 / FOP / BMP / ALK2 / 骨形成 / 進行性骨化性線維異形成症(FOP)

Outline of Final Research Achievements

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease, which is characterized by postnatal progressive heterotopic ossification in skeletal muscle through endochondral ossification. ALK2(R206H), a gain-of-function mutant of BMP type I receptor ALK2, have been found in patients with FOP, activates downstream signaling and induces heterotopic ossification. We have generated transgenic mice, in which ALK2(R206H) is expressed under the control of Cre/LoxP system. In the present study, we established a new model of chondrogenesis in vitro using the skeletal muscle cells prepared from ALK2(R206H) Tg mice. In conclusion, we established a new model of chondrogenesis using skeletal muscle cells. This in vitro model may be a useful tool to clarify the pathological mechanism of FOP and to develop a new treatment for FOP.

Research Products

• [Journal Article] Mutant activin-like kinase 2 in fibrodysplasia ossificans progressiva are activated via T203 by BMP type II receptor (2015)
  • Author(s): Fujimoto M, Ohte S, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Suda N, Katagiri T
  • Journal Title: Mol Endocrinol Volume: 29 Issue: 1 Pages: 140-152
  • DOI: 10.1210/me.2014-1301
  • Peer Reviewed / Open Access
• [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] Establishment of a novel model of chondrogenesis using murine embryonic stem cells carrying fibrodysplasia ossificans progressiva-associated mutant ALK2. (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Osawa K, Miyamoto A, Tsukamoto S, Mizuta T, Kokabu S, Machiya A, Okuda A, Suda N, Katagiri T.
  • Journal Title: Biochmical and Biophysical Research Communications Volume: 455 Issue: 3-4 Pages: 347-352
  • DOI: 10.1016/j.bbrc.2014.11.012
  • 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
• [Presentation] Establishment of a new model of chondrogenesis using skeletal muscle cells (2014)
  • Author(s): Miyamoto A, Osawa K, Tsukamoto S, Fujimoto M, Mizuta T, Ohte S, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 30th Anniversary Hall, Hidaka Campus, Saitama Medical University (埼玉県日高市）
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Establishment of a new in vivo experimental model for heterotopic bone formation in skeletal muscle. (2014)
  • Author(s): Osawa K, Tsukamoto S, Fujimoto M, Miyamoto A, Mizuta T, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 30th Anniversary Hall, Hidaka Campus, Saitama Medical University (埼玉県日高市）
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Chondrogenic differentiation of murine embryonic stem cells carrying an active form of ALK2. (2014)
  • Author(s): Fujimoto M, Ohte S, Shin M, Yoneyama K, Mizuta T, Osawa K, Tsukamoto S, Miyamoto A, Okuda A, Suda N, Katagiri T
  • Organizer: The 12th RCGM International Symposium of Academic Frontier
  • Place of Presentation: 30th Anniversary Hall, Hidaka Campus, Saitama Medical University (埼玉県日高市）
  • Year and Date: 2014-10-31 – 2014-11-01
• [Presentation] Tet-offシステムを用いたBMP受容体ALK2発現ES細胞の樹立と機能解析。 (2014)
  • Author(s): 藤本舞、大澤賢次、宮本阿礼、古株彰一郎、須田直人、片桐岳信
  • Organizer: 第56回歯科基礎医学会学術大会
  • Place of Presentation: 福岡国際会議場 (福岡県福岡市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] マウス骨格筋由来細胞によるALK2(R206H)の新しい解析法の樹立 (2013)
  • Author(s): 宮本阿礼、大澤賢次、塚本翔、藤本舞、水田誉人、片桐岳信
  • Organizer: 埼玉医科大学ゲノム医学研究センター(RCGM) 第11回RCGMフロンティアシンポジウム
  • Place of Presentation: 埼玉医科大学 日高キャンパス 創立30周年記念講堂 （ 埼玉県 日高市）
• [Presentation] 進行性骨化性線維異形成症の典型症例および亜型症例から同定されたALK2受容体はII型受容体に体する感受性が異なる (2013)
  • Author(s): 藤本舞、大手聡、塚本翔、宮本阿礼、古株彰一郎、須田直人、片桐岳信
  • Organizer: 第31回 日本骨代謝学会学術集会
  • Place of Presentation: 神戸国際展示場 （ 兵庫県 神戸市）
• [Presentation] Mutant ALK2 Receptors Identified In Patients With A Typical And A Variant Fibrodysplasia Ossificans Progressiva Show Different Sensitivities To Type II Receptors (2013)
  • Author(s): Mai Fujimoto, Satoshi Ohte, Sho Tsukamoto, Arei Miyamoto, Naoto Suda, Takenobu Katagiri
  • Organizer: 2nd Joint Meeting of the International Bone and Mineral Society
  • Place of Presentation: Kobe international conference center （ 兵庫県 神戸市）
• [Remarks] 埼玉医科大学 病態生理部門
  • URL: http://www.saitama-med.ac.jp/genome/Div04_PPhysiol/index.html
• [Remarks] 進行性骨化性繊維異形成症（ＦＯＰ）に関する調査研究班
  • URL: http://fop.umin.jp/
• [Remarks] 埼玉医科大学FOP診療・研究プロジェクト
  • URL: http://www.saitama-med.ac.jp/medlinks/saitama_univ_fop/