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2017 Fiscal Year Annual Research Report

Development of therapeutic drugs for fibrodysplasia ossificans progressiva by drug repositioning strategies

Research Project

Project/Area Number 15K15548
Research InstitutionNagoya University

Principal Investigator

鬼頭 浩史  名古屋大学, 医学系研究科, 准教授 (40291174)

Co-Investigator(Kenkyū-buntansha) 杉浦 洋  名古屋大学, 医学部附属病院, 医員 (40750477) [Withdrawn]
松下 雅樹  名古屋大学, 医学部附属病院, 病院助教 (60721115)
Project Period (FY) 2015-04-01 – 2018-03-31
Keywords進行性骨化性線維異形成症 / ドラッグスクリーニング / 異所性骨化 / Id1 / ALK2
Outline of Annual Research Achievements

C2C12細胞に変異型ALK2ベクター、レニーラ・ルシフェラーゼベクターおよびId1プロモータールシフェラーゼベクターを遺伝子導入したスクリーニング系を確立した。その系を用いてFDA許認可薬のパネルを用いて網羅的な薬効スクリーニングを実施し、4種類の抗うつ薬(ノリトレン、アナフラニール、プロチアデン、トリミプラミン)、3種類の抗ヒスタミン薬(ヒスマナール、アゼプチン、クラリチン)、3種類の抗精神病薬(スピペロン、ロドピン、インプロメン)、その他ジヒデルゴット(セロトニン作動薬)、ペルジピン(高血圧薬)、オーラノフィン(抗リウマチ薬)、ローコール(高脂血症薬)、エビスタ(骨粗鬆症薬)を候補薬として同定した。このうち、MTSアッセイにより細胞増殖能を評価したところ、アゼプチン、ローコール、アナフラニール、トリミプラミン、スピペロンの5薬剤が細胞増殖能を保ちながらルシフェラーゼ活性を低下させた。これら5薬剤に対してサードスクリーニングにてルシフェラーゼ活性の薬剤濃度依存性を検討したところ、アナフラニールとスピペロンでは濃度依存性を認めなかった。そこでアゼプチン、ローコール、トリミプラミンの3薬剤に対し、Id1のmRNAの発現をRT-PCR法で、Id1タンパクの発現をWestern blotting法にて評価したところ、いずれもmRNAレベルでの抑制は認められたが、タンパクレベルでの抑制は明らかではなかった。また、Id1の標的遺伝子である各種骨形成マーカー(アルカリフォスファターゼ、オステオカルシン、オステオポンチンなど)のmRNAおよびタンパク発現を検討し、一部では抑制効果を認めたものの、候補薬剤を決定するほどのin vitroでの有効性を得ることはできなかった。次いで、crude BMPの筋肉内移植による異所性骨化モデルラットにそれぞれの薬剤を経口投与して、in vivoにおける骨形成抑制効果を評価した。

  • Research Products

    (25 results)

All 2018 2017

All Journal Article (9 results) (of which Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (16 results) (of which Int'l Joint Research: 16 results,  Invited: 4 results)

  • [Journal Article] Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia2018

    • Author(s)
      Okura T, Matsushita M, Mishima K, Esaki R, Seki T, Ishiguro N, Kitoh H
    • Journal Title

      J Orthop Res

      Volume: 36 Pages: 300-308

    • DOI

      10.1002/jor.23608.

    • Peer Reviewed / Open Access
  • [Journal Article] Chronic lateral epiphyseal separation of the proximal tibia causes late-onset tibia vara2018

    • Author(s)
      Hasegawa S, Kitoh H, Matsushita M, Mishima K, Kadono I, Sugiura H, Kitamura A, Ishiguro N
    • Journal Title

      J Pediatr Orthop B

      Volume: 27 Pages: 31-34

    • DOI

      10.1097/BPB.0000000000000430.

    • Peer Reviewed / Open Access
  • [Journal Article] Early radiographic risk factors for rigid relapse in idiopathic clubfoot treated with the Ponseti method2018

    • Author(s)
      Mishima K, Kitoh H, Matsushita M, Sugiura H, Hasegawa S, Kitamura A, Nishida Y, Ishiguro N
    • Journal Title

      Foot Ankle Surg

      Volume: ― Pages: ―

    • DOI

      10.1016/j.fas.2017.06.003.

    • Peer Reviewed / Open Access
  • [Journal Article] Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva2018

    • Author(s)
      Nakahara Y, Kitoh H, Nakashima Y, Toguchida J, Haga N
    • Journal Title

      Disabil Rehabil

      Volume: ― Pages: ―

    • DOI

      10.1080/09638288.2017.1405083.

  • [Journal Article] Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia2017

    • Author(s)
      Matsushita M, Mishima K, Esaki R, Ishiguro N, Ohno K, Kitoh H
    • Journal Title

      J Neurosurg Pediatr

      Volume: 19 Pages: 91-95

    • DOI

      10.3171/2016.7.PEDS16199.

    • Peer Reviewed / Open Access
  • [Journal Article] Is the timing of surgery associated with avascular necrosis after unstable slipped capital femoral epiphysis ? : A multicenter study2017

    • Author(s)
      Kohno Y, Nakashima Y, Kitano T, Irie T, Kita A, Nakamura T, Endo H, Fujii Y, Kuroda T, Mitani S, Kitoh H, Matsushita M, Hattori T, Iwata K, Iwamoto Y
    • Journal Title

      J Orthop Sci

      Volume: 22 Pages: 112-115

    • DOI

      10.1016/j.jos.2016.08.012.

    • Peer Reviewed / Open Access
  • [Journal Article] Percutaneous pinning after prolonged skeletal traction with the hip in a flexed position for unstable slipped capital femoral epiphysis2017

    • Author(s)
      Matsushita M, Mishima K, Iwata K, Hattori T, Ishiguro N, Kitoh H
    • Journal Title

      Medicine

      Volume: 96 Pages: e6662

    • DOI

      10.1097/MD.0000000000006662.

    • Peer Reviewed / Open Access
  • [Journal Article] Activated FGFR3 promotes bone formation via accelerating endochondral ossification in mouse model of distraction osteogenesi2017

    • Author(s)
      Osawa Y, Matsushita M, Hasegawa S, Esaki R, Fujio M, Ohgasawara B, Ishiguro N, Ohno K, Kitoh H
    • Journal Title

      Bone

      Volume: 105 Pages: 42-49

    • DOI

      10.1016/j.bone.2017.05.016.

    • Peer Reviewed / Open Access
  • [Journal Article] Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia2017

    • Author(s)
      Matsushita M, Esaki R, Mishima K, Ishiguro N, Ohno K, Kitoh H
    • Journal Title

      Sci Rep

      Volume: 7 Pages: 7371

    • DOI

      10.1038/s41598-017-07044-8.

    • Peer Reviewed / Open Access
  • [Presentation] Bone formation was promoted in mouse model of distraction osteogenesis with gain-of-function mutations in Fgfr32018

    • Author(s)
      Yusuke Osawa, Masaki Matsushita, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno, Hiroshi Kitoh
    • Organizer
      Annual meeting of Orthopaedic Research Society
    • Int'l Joint Research
  • [Presentation] Transplantation of autologous culture-expanded bone marrow cells and platelet rich plasma for bone regeneration. Comprehensive clinical study of the lower limb lengthening2017

    • Author(s)
      Hiroshi Kitoh, Kenichi Mishima, Masaki Matsushita, Hiroshi Sugiura, Akiko Kitamura, Naoki Ishiguro
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Clinical feasibility of meclozine for improvement of short stature in achondroplasia2017

    • Author(s)
      Masaki Matsushita, Hiroshi Kitoh, Kenichi Mishima, Hiroshi Sugiura, Akiko Kitamura, Naoki Ishiguro
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Long term health-related quality of life in achonroplasia2017

    • Author(s)
      Masaki Matsushita, Hiroshi Kitoh, Kenichi Mishima, Satoshi Yamashita, Hiroshi Sugiura, Akiko Kitamura, Naoki Ishiguro
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Disappearance of soft tissue interposition after gradual reduction using overhead traction in late-presenting DDH. A prospective comparative study on serial MRIs between pre-walking and walking children2017

    • Author(s)
      Hiroshi Kaneko, Tadashi Hattori, Koji Iwata, Masaki Matsushita, Hiroki Furuhashi, Hiroshi Kitoh
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Secondary spherical remodeling from the healed stage to skeletal maturity in Legg-Calve-Perthes Disease treated with Salter innominate osteotomy2017

    • Author(s)
      Hiroshi Kaneko, Hiroshi Kitoh, Masaki Matsushita, Hiroki Furuhashi, Tadashi Hattori
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Salter innominate osteotomy for DDH in childhood does not predispose to anterior over-coverage and posterior under-coverage in adulthood2017

    • Author(s)
      Hiroki Furuhashi, Hiroshi Kaneko, Koji Iwata, Tadashi Hattori, Hiroshi Kitoh
    • Organizer
      EPOS/POSNA combined annual meeting
    • Int'l Joint Research
  • [Presentation] Transplantation of autologous culture-expanded bone marrow cells and platelet rich plasma during lower limb lengthening2017

    • Author(s)
      Hiroshi Kitoh, Kenichi Mishima, Masaki Matsushita, Naoki Ishiguro
    • Organizer
      The 27th Korean-Japanese Combined Orthopaedic Symposium
    • Int'l Joint Research / Invited
  • [Presentation] Clinically feasible dose of meclozine improves bone growth, bone volume, and bone quality in mouse model with achondroplasia2017

    • Author(s)
      Masaki Matsushita, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno, Hiroshi Kitoh
    • Organizer
      The 27th Korean-Japanese Combined Orthopaedic Symposium
    • Int'l Joint Research
  • [Presentation] Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia2017

    • Author(s)
      Toshiaki Okura, Masaki Matsushita, Kenichi Mishima, Ryusaku Esaki, Taisuke Seki, Naoki Ishiguro, Hiroshi Kitoh
    • Organizer
      The 27th Korean-Japanese Combined Orthopaedic Symposium
    • Int'l Joint Research
  • [Presentation] Activated FGFR3 promotes bone formation via accelerating endochondral ossification in mouse model of distraction osteogenesis2017

    • Author(s)
      Yusuke Osawa, Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Hiroshi Kitoh
    • Organizer
      The 27th Korean-Japanese Combined Orthopaedic Symposium
    • Int'l Joint Research
  • [Presentation] Oral administration of meclozine for the treatment of short stature in achondroplasia2017

    • Author(s)
      Hiroshi Kitoh, Masaki Matsushita, Kenichi Mishima, Naoki Ishiguro, Kinji Ohno
    • Organizer
      The 13th International Skeletal Dysplasia Meeting
    • Int'l Joint Research
  • [Presentation] Treatment of deformities in lower extremity by a multi-axial external fixation system2017

    • Author(s)
      Masaki Matsushita, Hiroshi Kitoh, Kenichi Mishima, Naoki Ishiguro
    • Organizer
      The 61st Korean Orthopaedic Association
    • Int'l Joint Research
  • [Presentation] 培養骨髄細胞と多血小板血漿の移植を併用した下肢骨延長術2017

    • Author(s)
      鬼頭浩史、石黒直樹
    • Organizer
      第11回骨軟骨フロンティア
    • Int'l Joint Research / Invited
  • [Presentation] 小児整形外科領域における骨系統疾患2017

    • Author(s)
      鬼頭浩史
    • Organizer
      第10回胎児骨系統疾患フォーラム学術講演会
    • Int'l Joint Research / Invited
  • [Presentation] 骨髄間葉系幹細胞とPRPを用いた骨延長術2017

    • Author(s)
      鬼頭浩史、三島健一、松下雅樹、石黒直樹
    • Organizer
      第2回JAPSAM幹細胞研究会
    • Int'l Joint Research / Invited

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Published: 2018-12-17  

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