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Investigation of osteochondral function via activation of FGFR3 signaling

Research Project

Project/Area Number 17H04312
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionNagoya University

Principal Investigator

Kitoh Hiroshi  名古屋大学, 医学部, 招へい教員 (40291174)

Co-Investigator(Kenkyū-buntansha) 三島 健一  名古屋大学, 医学部附属病院, 講師 (40646519)
松下 雅樹  名古屋大学, 医学系研究科, 寄附講座助教 (60721115)
長田 侃  名古屋大学, 医学部附属病院, 医員 (80815324)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2017: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
KeywordsFGFR3 / 骨軟骨機能 / 軟骨無形成症 / 骨延長 / 変形性関節症 / 塩酸メクリジン / 薬効薬理作用 / 骨再生 / 軟骨変性 / 骨伸長 / モデルマウス / 骨延長術
Outline of Final Research Achievements

We demonstrated that new bone formation was accelerated during limb lengthening surgery and cartilage degeneration was inhibited via suppressing subchondral bone sclerosis in transgenic mice expressing activated fGFR3 signaling. We concluded that FGFR3 has a positive effect of bone regeneration and joint cartilage preservation. On the other hand, although it is known that FGFR3 signaling suppresses longitudinal bone growth, meclizine, which we found as a drug of FGFR3 inhibitor, significantly promoted bone growth in mice carrying a FGFR3 activating mutation. We determined that the optimal dose of meclizine on bone growth was 2mg/kg/day, and the minimal hepatotoxicity dose of meclizine was 8 mg/kg/day.

Academic Significance and Societal Importance of the Research Achievements

FGFR3の異常活性化によって発症する難病である軟骨無形成症において、動物モデルを使用して病態メカニズムを解明した。また、根本的治療薬となり得る塩酸メクリジンの動物モデルにおける至適用量と毒性を示す最小用量を同定した。前者は、軟骨無形成症患者の治療(骨延長術)および成人期における問題(変形性関節症)に対する治療介入に対する有用な情報を与えることができる。後者は、医師主導治験にむけたメクリジンのFGFR3抑制作用に関する有効性を示すエビデンスとなり得る。ヒトにおける難病を動物モデルを使用して病態メカニズムを解明し、新たな治療法の開発に結びつく研究であり、社会的意義は大きいと思われる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (44 results)

All 2020 2019 2018 2017

All Journal Article (20 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 20 results,  Open Access: 16 results) Presentation (23 results) (of which Int'l Joint Research: 18 results,  Invited: 9 results) Book (1 results)

  • [Journal Article] Fibrodysplasia ossificans progressiva: Review and research activities in Japan2020

    • Author(s)
      Haga Nobuhiko、Nakashima Yasuharu、Kitoh Hiroshi、Kamizono Junji、Katagiri Takenobu、Saijo Hideto、Tsukamoto Sho、Shinoda Yusuke、Sawada Ryoko、Nakahara Yasuo
    • Journal Title

      Pediatrics International

      Volume: 62 Issue: 1 Pages: 3

    • DOI

      10.1111/ped.14065

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of fracture characteristics and disease-specific complications on health-related quality of life in osteogenesis imperfecta2020

    • Author(s)
      Matsushita M, Mishima K, Yamashita S, Haga N, Fujiwara S, Ozono K, Kubota T, Kitaoka T, Ishiguro N, Kitoh H
    • Journal Title

      J Bone Miner Metab

      Volume: 38 Issue: 1 Pages: 109-116

    • DOI

      10.1007/s00774-019-01033-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report.2020

    • Author(s)
      Nagata T, Matsushita M, Mishima K, Kamiya Y, Kato K, Toyama M, Ogi T, Ishiguro N, Kitoh H.
    • Journal Title

      Molecular Genetics & Genomic Medicine

      Volume: 8 Issue: 3 Pages: 1-1

    • DOI

      10.1002/mgg3.1148

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia2019

    • Author(s)
      Matsushita Masaki、Kitoh Hiroshi、Mishima Kenichi、Yamashita Satoshi、Haga Nobuhiko、Fujiwara Sayaka、Ozono Keiichi、Kubota Takuo、Kitaoka Taichi、Ishiguro Naoki
    • Journal Title

      Calcified Tissue International

      Volume: 104 Issue: 4 Pages: 364-372

    • DOI

      10.1007/s00223-019-00518-z

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lower limb pain following allogeneic hematopoietic stem cell transplantation in Japanese children2019

    • Author(s)
      Mishima Kenichi、Kitoh Hiroshi、Matsushita Masaki、Nagata Tadashi、Kamiya Yasunari、Takahashi Yoshiyuki、Ishiguro Naoki
    • Journal Title

      Journal of Orthopaedic Science

      Volume: 26 Issue: 4 Pages: 1-1

    • DOI

      10.1016/j.jos.2019.07.007

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of surgical and nonsurgical containment methods for patients with Legg-Calv?-Perthes disease of the onset ages between 6.0 and 8.0 years2019

    • Author(s)
      Kaneko Hiroshi、Kitoh Hiroshi、Mishima Kenichi、Matsushita Masaki、Hattori Tadashi、Noritake Koji、Ishiguro Naoki、Yoshihashi Yuji
    • Journal Title

      Journal of Pediatric Orthopaedics B

      Volume: - Issue: 6 Pages: 1-1

    • DOI

      10.1097/bpb.0000000000000710

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Mouse Distraction Osteogenesis Model2018

    • Author(s)
      Fujio Masahito、Osawa Yusuke、Matsushita Masaki、Ogisu Kota、Tsuchiya Shuhei、Kitoh Hiroshi、Hibi Hideharu
    • Journal Title

      Journal of Visualized Experiments

      Volume: 141 Issue: 141 Pages: 0-0

    • DOI

      10.3791/57925

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel heterozygous mutation in the T-box protein 4 gene in an adult case of small patella syndrome2018

    • Author(s)
      Oda T, Matsushita M, Ono Y, Kitoh H, Sakai T
    • Journal Title

      J Orthop Case Rep

      Volume: 8 Pages: 85-88

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chronic lateral epiphyseal separation of the proximal tibia causes late-onset tibia vara.2018

    • 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 Issue: 1 Pages: 31-34

    • DOI

      10.1097/bpb.0000000000000430

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Changes in the range of motion of the lower limb joints during extensive tibial lengthening in achondroplasia2018

    • Author(s)
      Kadono Izumi、Kitoh Hiroshi、Mishima Kenichi、Matsushita Masaki、Sato Koji、Kako Masato、Ishiguro Naoki
    • Journal Title

      Journal of Pediatric Orthopaedics B

      Volume: 27 Issue: 6 Pages: 535-540

    • DOI

      10.1097/bpb.0000000000000526

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Congenital limb deficiency in Japan: a cross-sectional nationwide survey on its epidemiology2018

    • Author(s)
      Mano Hiroshi、Fujiwara Sayaka、Takamura Kazuyuki、Kitoh Hiroshi、Takayama Shinichiro、Ogata Tsutomu、Hashimoto Shuji、Haga Nobuhiko
    • Journal Title

      BMC Musculoskeletal Disorders

      Volume: 19 Issue: 1 Pages: 262-262

    • DOI

      10.1186/s12891-018-2195-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Extensive Bone Lengthening for a Patient with Linear Morphea2018

    • Author(s)
      Mishima K, Kitoh H, Matsushita M, Nagata T, Kamiya Y, Ishiguro N.
    • Journal Title

      Case Rep Orthop.

      Volume: - Pages: 1-5

    • DOI

      10.1155/2018/4535804

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia.2018

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

      J Orthop Res

      Volume: 36(1) Issue: 1 Pages: 300-308

    • DOI

      10.1002/jor.23608

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva2017

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

      Disabil Rehabil

      Volume: 41 Issue: 6 Pages: 699

    • DOI

      10.1080/09638288.2017.1405083

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activated FGFR3 promotes bone formation via accelerating endochondral ossification in mouse model of distraction osteogenesis2017

    • Author(s)
      Osawa Yusuke、Matsushita Masaki、Hasegawa Sachi、Esaki Ryusaku、Fujio Masahito、Ohkawara Bisei、Ishiguro Naoki、Ohno Kinji、Kitoh Hiroshi
    • Journal Title

      Bone

      Volume: 105 Pages: 42-49

    • DOI

      10.1016/j.bone.2017.05.016

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early radiographic risk factors for rigid relapse in idiopathic clubfoot treated with the Ponseti method.2017

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

      Foot Ankle Surg.

      Volume: ー Issue: 6 Pages: 30126-1

    • DOI

      10.1016/j.fas.2017.06.003

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [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 Issue: 1 Pages: 91-95

    • DOI

      10.3171/2016.7.peds16199

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Is the timing of surgery associated with avascular necrosis after unstable slipped capital femoral epiphysis? A multicenter study.2017

    • 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 Issue: 1 Pages: 112-115

    • DOI

      10.1016/j.jos.2016.08.012

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Percutaneous pinning after prolonged skeletal traction with the hip in a flexed position for unstable slipped capital femoral epiphysis: A case series of 11 patients.2017

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

      Medicine (Baltimore).

      Volume: 96 Issue: 19 Pages: e6662-e6662

    • DOI

      10.1097/md.0000000000006662

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia.2017

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

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 7371-7371

    • DOI

      10.1038/s41598-017-07044-8

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Current techniques to prevent avascular necrosis in unstable slipped capital femoral epiphysis2019

    • Author(s)
      Hiroshi Kitoh, Tadashi Hattori, Masaki Matsushita, Kenichi Mishima
    • Organizer
      12th Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Diagnosis and treatment of a rare disease in orthopaedic clinical practice: hypophosphatasia -a treatable disease not to be missed-2019

    • Author(s)
      Hiroshi Kitoh. Diagnosis and treatment of a rare disease in orthopaedic clinical practice: hypophosphatasia -a treatable disease not to be missed-
    • Organizer
      12nd Combined Meeting of Asia Pacific Spine Society & Asia Pacific Paediatric Orthopaedic Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 骨系統疾患における成人期以降の問題点2019

    • Author(s)
      鬼頭浩史、三島健一、松下雅樹、長田侃、神谷庸成、石黒直樹
    • Organizer
      第92回日本整形外科学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 軟骨無形成症治療薬の開発―医師主導治験の実施―2019

    • Author(s)
      鬼頭浩史、松下雅樹、三島健一、長田侃、神谷庸成
    • Organizer
      第30回日本小児整形外科学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Bone formation was promoted in mouse model of distraction osteogenesis with gain-of-function mutations in Fgfr32018

    • Author(s)
      Osawa Y, Matsushita M, Mishima K, Ishiguro N, Ohno K, Kitoh H
    • Organizer
      Annual meeting of Orthopaedic Research Society
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Transplantation of autologous culture-expanded bone marrow cells and PRP during lower limb lengthening2018

    • Author(s)
      Kitoh H
    • Organizer
      Asia Pacific Stem Cells and Cartilage Repair Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Long-term health-related quality of life in patients with achondroplasia and hypochondroplasia2018

    • Author(s)
      11.Matsushita M, Kitoh H, Mishima K, Ishiguro N, Fujiwara S, Haga N, Kitaoka T, Kubota T, Ozono K
    • Organizer
      Annual meeting of the American Society for Bone and Mineral Research
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • 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
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Book] TEXT整形外科学改訂5版 第8章 骨・関節系統疾患2019

    • Author(s)
      鬼頭浩史
    • Total Pages
      486
    • Publisher
      南江堂
    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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