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Reevaluation of osteoporosis therapies based on the site-specificresponse of bone cells derived from lower limb, mandibular and calvarial bones to mechanical stimuli.

Research Project

Project/Area Number 22616009
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Mechanobiology
Research InstitutionKanagawa Dental College

Principal Investigator

MIKUNI-TAKAGAKI Yuko  神奈川歯科大学, 歯学部, 教授 (60050689)

Project Period (FY) 2010 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2012: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords骨粗鬆症 / 顎骨壊死 / 力学的刺激 / LIPUS / アポトーシス / リモデリング / 骨芽細胞 / 神経堤(neural crest) / 骨細胞 / 不動 / 胚葉
Research Abstract

While astronauts and bed-rest patients lose weight-bearing bone by almost one percent a month, non-weight-bearing bone is insensitive to unloading. It is unclear how bone cells at different sites detect mechanical loading/unloading and how site-specific mechanotransduction affects bone homeostasis. The aim of this study is to re-evaluate our understanding of osteoporosis and its treatment in terms of the response to the mechanical environment by bone cells at different sites. To differentiate the anabolic mechanical response of mandibular cells from those of calvarial and long-bone cells, we isolated mouse osteoblasts and subjected them to therapeutic low intensity pulsed ultrasound (LIPUS). Our results showed the following:1. While LIPUS-accelerated differentiation is universal among the osteoblasts ofdifferent origin, the mandible needs mechanical stimuli for RANKL expression/remodeling and survival.2. In mandibular and long-bone osteoblasts, ILK lies upstream of PI3K/Akt but downstr … More eam from α5β1 integrin, which is indispensable for the response to LIPUS.3. In calvaria, the up-regulation by LIPUS is not significant except in β-catenin.While the calvaria shares ectodermal origin with the mandibular bone, it may notneed mechanotransduction for such anabolic reactions.4. In mandible, anti-α5β1 Ab completely blocks the up-regulation of LIPUS.5. The role of α5β1 integrin as a gate keeper may have evolved to protect jaw bones from unfavorable responses to the inflammatory cytokines arising from periodontal pathology in the absence of mechanical stimuli.These findings indicate that the cellular environment, in addition to the tridermic origin, determines site-specific bone homeostasis through the remodeling of bone and the survival of osteoblasts. Differentiated cells of the osteoblastic lineage at different bone sites transmit signals through transmembrane integrins such as α5β1 integrin in case of mandibular osteoblasts, whose signaling pathways are influenced by environmental factors such as inflammatory cytokines produced in response to bacteria. To further delineate the unique oral mechanical defense system, which we believe may fail by bisphosphonate administration resulting in osteonecrosis of the jaw (ONJ), we developed a rat ONJ model that was subjected to LIPUS, which provided an alternative mechanical stress for the biting force. As a result, we were able to show the efficacy of LIPUS, which prevented the onset of ONJ in themodel system we developed. Less

Report

(4 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (35 results)

All 2013 2012 2011 2010

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (21 results) Book (3 results)

  • [Journal Article] Static and Dynamic Hypergravity Responses of Osteoblasts and Osteoclasts in Medaka Scales2013

    • Author(s)
      Yano S, et al. (14番目)
    • Journal Title

      Zoological Science

      Volume: 30 Issue: 3 Pages: 217-223

    • DOI

      10.2108/zsj.30.217

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Repeated freeze-thaw cycles reduce the survival rate of osteocytes in bone-tendon constructs without affecting the mechanicalproperties of tendons2012

    • Author(s)
      Suto K, Urabe K, Naruse K, Uchida K, Matsuura T, Mikuni-Takagaki Y, Suto M, Nemoto N, Kamiya K and Itoman M
    • Journal Title

      Cell Tissue Bank

      Volume: Vol.13,No.1 Issue: 1 Pages: 71-80

    • DOI

      10.1007/s10561-010-9234-0

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] A novel underuse model shows that inactivity but not ovariectomy determines the deteriorated material properties and geometry of cortical bone in the tibia of adult rats2011

    • Author(s)
      Miyagawa K, Kozai Y, Ito Y, Furuhama T, Naruse K, Nonaka K, Nagai Y, Yamato H, Kashima I, Ohya K, Aoki K, Mikuni-Takagaki Y
    • Journal Title

      J BoneMiner Metab

      Volume: Vol.29,No.4 Issue: 4 Pages: 422-436

    • DOI

      10.1007/s00774-010-0241-9

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Low-intensity pulsed ultrasound promotes the osteogenic effectinduced by bone allograft2011

    • Author(s)
      Aikawa J,Naruse K,Uchida K,Katano M, Mikuni-Takagaki Y, Kozai Y, Kashima I, Takaso M,ltoman M,Urabe K
    • Journal Title

      Kitasato Med J

      Volume: Vol.41 Pages: 184-192

    • URL

      http://mlib.kitasato-u.ac.jp/homepage/ktms/kaishi/pdf/KMJ41-2/KMJ41-2p184-192.pdf.

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] MechanotransductionActivates α5β1 Integrin and PI3K/Akt Signaling Pathways in Mandibular Osteoblasts2011

    • Author(s)
      Watabe H, Furuhama T, Tani-Ishii N, andMikuni-Takagaki Y
    • Journal Title

      Exp Cell Res

      Volume: Vol.317,No.18 Issue: 18 Pages: 12642-12649

    • DOI

      10.1016/j.yexcr.2011.07.015

    • Related Report
      2012 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Low Intensity Pulsed Ultrasound Accelerates Delayed Healing Process by Reducing the Time Required for the Completion of Endochondral Ossification in the Aged Mouse Femur Fracture Model2011

    • Author(s)
      Katano M, Naruse K, Uchida K, Mikuni-Takagaki Y, et al
    • Journal Title

      Experimental Animals

      Volume: 60 Issue: 4 Pages: 385-395

    • DOI

      10.1538/expanim.60.385

    • NAID

      10029550747

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Low-intensity pulsed ultrasound promotes the osteogenic effeet induced by bone allograft2011

    • Author(s)
      Aikawa J, Naruse K, Uchida K, Katano M, Mikuni-Takagaki Y, et al
    • Journal Title

      Kitasato Med J

      Volume: 41 Pages: 184-192

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel underuse model shows that inactivity but not ovariectomy determines the deteriorated material properties and geometry of cortical bone in the tibia of adult rats.2011

    • Author(s)
      Miyagawa K, et al(12番目/12)
    • Journal Title

      J Bone Miner Metab

      Volume: 29(in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Repeated freeze-thaw cycles reduce the survival rate of osteocytes in bone-tendon constructs without affecting the mechanical properties of tendons.2011

    • Author(s)
      Suto K, et al(6番目/10)
    • Journal Title

      Cell Tissue Bank

      Volume: 12(in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prolonged endo- chondral bone healing in senescence is shortened by low-intensity pulsed ultrasound in a manner dependent on COX-22010

    • Author(s)
      Naruse K, Sekiya H, Harada Y, Iwabuchi S, Kozai Y, Kawamata R, Kashima I, Uchida K, Urabe K, Seto K, Itoman M, Mikuni-Takagaki Y
    • Journal Title

      Ultrasound Med Biol

      Volume: vol.36,No.7 Issue: 7 Pages: 1098-1108

    • DOI

      10.1016/j.ultrasmedbio.2010.04.011

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Prolong endochondral bone healing in senescence is shortened by low-intensity pulsed ultrasound in a manner dependent on COX-2.2010

    • Author(s)
      Naruse K, et al(12番目/12)
    • Journal Title

      Ultrasound Med Biol

      Volume: 36 Pages: 1098-1108

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] 顎骨壊死モデルラット作成とLIPUSによる防止の試み2013

    • Author(s)
      田中隆博,渡部弘隆,河田亮,佐藤武則,船山祐太,田島愛弓,浜田信城,石井信之,寺中敏夫,高垣裕子
    • Organizer
      第16回超音波骨折治療研究会
    • Place of Presentation
      東京
    • Year and Date
      2013-01-19
    • Related Report
      2012 Annual Research Report 2012 Final Research Report
  • [Presentation] Mechanotransduction Regulates Metabolism of Mouse Mandible Bone2012

    • Author(s)
      Y Mikuni-Takagaki
    • Organizer
      Exogen Think Tank Meeting
    • Place of Presentation
      Durham, NC, USA
    • Year and Date
      2012-08-28
    • Related Report
      2012 Final Research Report
  • [Presentation] 神経堤由来の下顎骨における力学刺激依存性の骨代謝2012

    • Author(s)
      渡部弘隆,河田亮,船山祐太,田島愛弓,石井信之,高垣裕子
    • Organizer
      第30回日本骨代謝学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2012-07-21
    • Related Report
      2012 Annual Research Report 2012 Final Research Report
  • [Presentation] 運動不足・身体的不活動(physicalinactivity)と廃用性の骨粗鬆症モデル2012

    • Author(s)
      高垣裕子
    • Organizer
      第4回骨形態フォーラム
    • Place of Presentation
      道後
    • Year and Date
      2012-06-23
    • Related Report
      2012 Final Research Report
  • [Presentation] 運動不足・身体的不活動(physical inactivity)と廃用性の骨粗鬆症モデル2012

    • Author(s)
      高垣裕子
    • Organizer
      第4回骨形態フォーラム
    • Place of Presentation
      松山
    • Year and Date
      2012-06-23
    • Related Report
      2012 Annual Research Report
  • [Presentation] 下顎骨における力学的刺激応答の特殊性2012

    • Author(s)
      田島愛弓, 河田亮, 渡部弘隆, 石井信之, 高垣裕子
    • Organizer
      神奈川歯科大学学会第138回例会
    • Place of Presentation
      横須賀
    • Year and Date
      2012-06-02
    • Related Report
      2012 Annual Research Report
  • [Presentation] マウス下顎骨骨芽細胞におけるLIPUS刺激依存性の骨代謝2012

    • Author(s)
      渡部弘隆、古濱貴美、船山祐太、石井信之、高垣裕子
    • Organizer
      第14回超音波骨折治療研究会
    • Place of Presentation
      東京
    • Year and Date
      2012-01-22
    • Related Report
      2012 Final Research Report 2011 Annual Research Report
  • [Presentation] 骨の部位に特異的な力学的刺激応答のメカニズム2011

    • Author(s)
      高垣裕子
    • Organizer
      第18回横浜・京都・奈良バイオメカニクスカンファレンス
    • Place of Presentation
      京都(招待講演)
    • Year and Date
      2011-12-17
    • Related Report
      2011 Annual Research Report
  • [Presentation] Is Alendronate Effective in Improving Material Properties of Frail Cortical Bone in Inactive Model Rats2011

    • Author(s)
      Suto M, Naruse K, Uchida K,Yamamoto T, Suto K, Urabe K, Itoman M, and Mikuni-Takagaki Y.
    • Organizer
      33th Annual Meeting of the AmericanSociety for Bone and Mineral Research
    • Place of Presentation
      San Diego, California
    • Year and Date
      2011-09-18
    • Related Report
      2012 Final Research Report
  • [Presentation] Influence of the difference in repetition frequency and intensity of low intensity pulsed ultrasound for cultured chondrocytes.2011

    • Author(s)
      Suzuki Y, Takeuchi R, Takagaki, YM, Shiraishi T, Fukui S, Morishita S
    • Organizer
      2011 World Congress on Osteoarthritis
    • Place of Presentation
      San Diego, California, USA
    • Year and Date
      2011-09-17
    • Related Report
      2012 Final Research Report
  • [Presentation] Influence of the difference in repetition frequency and intensity of low intensity pulsed ultrasound for cultured chondrocytes2011

    • Author(s)
      Suzuki Y, Takeuchi R, Takagaki, YM, Shiraishi T, Fukui S, Morishita S
    • Organizer
      2011 World Congress on Osteoarthritis
    • Place of Presentation
      San Diego, CA、USA
    • Year and Date
      2011-09-11
    • Related Report
      2011 Annual Research Report
  • [Presentation] 下顎骨骨芽細胞に特異的な、α5β1インテグリンとPI3K/Aktsigunaru伝達経路を介した力学刺激依存性の骨代謝.2011

    • Author(s)
      渡部弘隆,古濱貴美,石井信之,高垣裕子
    • Organizer
      第29回日本骨代謝学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2011-07-30
    • Related Report
      2012 Final Research Report
  • [Presentation] 下顎骨骨芽細胞に特異的な、α5β1インテグリンとPI3K/Akt sigunaru伝達経路を介した力学刺激依存性の骨代謝2011

    • Author(s)
      渡部弘隆, 古濱貴美, 石井信之, 高垣裕子
    • Organizer
      第29回日本骨代謝学会学術集会
    • Place of Presentation
      大阪
    • Year and Date
      2011-07-30
    • Related Report
      2011 Annual Research Report
  • [Presentation] Mechanical force may be a prerequisite for mandibular bone remodeling2011

    • Author(s)
      Watabe W, Furuhama T, Tani-Ishii N, Mikuni-Takagaki Y
    • Organizer
      IADR/AADR/CADR General Session
    • Place of Presentation
      San Diego, California, USA
    • Year and Date
      2011-03-19
    • Related Report
      2012 Final Research Report
  • [Presentation] Mechanical force may be a prerequisite for mandibular bone remodeling2011

    • Author(s)
      Watabe H, et al(4番目/4)
    • Organizer
      89th General Session, International Association for Dental Research
    • Place of Presentation
      San Diego Convention Center(米国サンディエゴ)
    • Year and Date
      2011-03-19
    • Related Report
      2010 Annual Research Report
  • [Presentation] マウス下顎骨骨芽細胞におけるLIPUS刺激依存性の骨代謝2011

    • Author(s)
      渡部弘隆,古濱貴美,船山祐太,石井信之,高垣裕子
    • Organizer
      第14回超音波骨折治療研究会
    • Place of Presentation
      東京
    • Year and Date
      2011-01-22
    • Related Report
      2012 Final Research Report
  • [Presentation] ビスフォスフォネート製剤投与ラットにおける顎骨壊死誘導モデルの作成-歯周炎誘発モデルにおける下顎骨の形態変化-.2010

    • Author(s)
      渡部弘隆,武藤徳子,佐藤武則,石井信之,高垣裕子
    • Organizer
      第133回日本歯科保存学会秋季学術大会
    • Place of Presentation
      岐阜
    • Year and Date
      2010-10-28
    • Related Report
      2012 Final Research Report
  • [Presentation] Differential Gene Expression in Osteoblast/Osteocyte Lineage Cells between Hyp Mouse and Wild-type Mouse.2010

    • Author(s)
      Miyagawa K, Ozono K, Tachikawa K, Mikuni-Takagaki Y, Kogo M and Michigami T
    • Organizer
      32th Annual Meeting of the American Society for Bone and Mineral Research
    • Place of Presentation
      Toronto, Canada
    • Year and Date
      2010-10-16
    • Related Report
      2012 Final Research Report
  • [Presentation] 下顎骨骨芽細胞による骨代謝の力学的刺激依存性.2010

    • Author(s)
      渡部弘隆,古濱貴美,石井信之,高垣裕子
    • Organizer
      第52回歯科基礎医学会学術大会・総会
    • Place of Presentation
      東京
    • Year and Date
      2010-09-22
    • Related Report
      2012 Final Research Report
  • [Presentation] C57B6Jマウス下顎骨骨芽細胞における力学的刺激応答の特異性2010

    • Author(s)
      古濱貴美,渡部弘隆,石井信之,高垣裕子
    • Organizer
      第28回日本骨代謝学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2010-07-23
    • Related Report
      2012 Final Research Report
  • [Presentation] C57B6Jマウス下顎骨骨芽細胞における力学的刺激応答の特異性2010

    • Author(s)
      古濱貴美, ら(4番目/4)
    • Organizer
      第28回日本骨代謝学会
    • Place of Presentation
      京王プラザホテル(東京)
    • Year and Date
      2010-07-23
    • Related Report
      2010 Annual Research Report
  • [Book] 低出力超音波刺激に対する細胞応答2013

    • Author(s)
      高垣裕子
    • Publisher
      金芳堂
    • Related Report
      2012 Final Research Report
  • [Book] ナノインデンテーション法2013

    • Author(s)
      高垣裕子,田中隆博
    • Publisher
      大樹舎
    • Related Report
      2012 Final Research Report
  • [Book] 低出力超音波刺激に対する細胞応答in生体電気・物理刺激による骨・軟部組織修復法2013

    • Author(s)
      高垣裕子
    • Publisher
      金芳堂
    • Related Report
      2012 Annual Research Report

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Published: 2010-08-23   Modified: 2019-07-29  

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