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Elucidation of molecular mechanism involved in mechanical stress signaling in bone - functional analysis, contribution to pathology, and cloning of related molecule of a novel gene Znt5 -

Research Project

Project/Area Number 15390451
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

KAWAGUCHI Hiroshi  The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (40282660)

Co-Investigator(Kenkyū-buntansha) HOSHI Kazuto  The University of Tokyo, Faculty of Medicine, visiting Associate Professor, 医学部附属病院, 客員助教授 (30344451)
NAKAMURA Kozo  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60126133)
TANAKA Toshihiro  RIKEN, (The Institute of Physical and Chemical Research), SNP Research Center, Team Leader, 遺伝子多型研究センター, チームリーダー (50292850)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000)
Keywordsmechanical stress / bone / osteoporosis / fracture / osteoarthritis / knockout mouse
Research Abstract

We recently isolated a novel gene Znt5 whose expression increased in response to expansion load of rabbit aorta. Znt5 functions as a zinc transporter and Znt5^<-/-> mice exhibited slight growth retardation and osteoporosis as compared to wild-type (WT) littermates. The bone loss seemed to be due to a dysfunction of osteoblasts. To learn the involvement of this molecule in the mechanical stress signaling in bone, we first examined the expression in bone responding to mechanical stress using several models. When three kinds of osteoblastic cell lines, MC3T3-E1,MLO-Y4 and MLO-A5,were cultured with stretching stimulation by the Flexor Cell system, about 2-fold increase of Znt5 expression was seen only in MLO-Y4 cells that are known to be the most differentiated osteoblasts. When three kinds of osteoblastic cell lines, MC3T3-E1,MLO-Y4 and MLO-A5,were cultured with stretching stimulation by the Flexor Cell system, about 2-fold increase of Znt5 expression was seen only in MLO-Y4 cells that ar … More e known to be the most differentiated osteoblasts. In the culture of mouse newborn calvariae, Znt5 expression was induced by continuous tensile stress by an inserted spring for 9 h. In the mouse tail suspension model, Znt5 mRNA level in tibiae and femora was decreased to about one third that of control after 3 weeks of unloading, and was restored to the normal level by reloading. When Znt5^<-/-> mice were treated with tail suspension for 3 weeks, the decrease in bone density (-5%) was much less than that in WT (-15%). In a tibial fracture model and an experimental knee OA model, fracture healing and cartilage destruction, respectively, was similarly seen in WT and Znt5^<-/-> mice. To explore the downstream signaling of Znt5,we compared the gene expression profile between Znt5^<-/-> and WT bones, and found that about 20 genes were decreased in Zn5^<-/->. However, real-time PCR analyses of those mRNA expressions revealed no significant differences between Znt5^<-/-> and WT. We conclude that Znt5, whose expression is positively regulated by mechanical stress in mature osteoblasts or osteocytes, plays an essential role in the maintenance of bone volume by mechanical stress. Less

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (14 results)

All 2005 2004 2003 Other

All Journal Article (11 results) Publications (3 results)

  • [Journal Article] 閉経後の骨粗鬆症の治療:治療薬の種類と作用機序2005

    • Author(s)
      篠田裕介, 川口浩
    • Journal Title

      Mebio 22(11)

      Pages: 92-97

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 性ホルモンと骨粗鬆症2005

    • Author(s)
      河野博隆, 川口浩
    • Journal Title

      リウマチ科 33(6)

      Pages: 654-661

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 原発性骨粗鬆症に関する最近の知見2004

    • Author(s)
      川口 浩
    • Journal Title

      Medical Practice 21(10)

      Pages: 1665-1669

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 移植による骨軟骨再生2004

    • Author(s)
      川口 浩
    • Journal Title

      治療学 38(10)

      Pages: 1120-1127

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 骨折治癒と成長因子・サイトカインシグナル2004

    • Author(s)
      川口 浩
    • Journal Title

      The Bone 18(6)

      Pages: 731-739

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 加齢に伴う骨粗鬆化の分子メカニズム2004

    • Author(s)
      川口 浩
    • Journal Title

      日本老年医学会雑誌 41(6)

      Pages: 612-615

    • NAID

      10014285579

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 再生医療:再生促進因子2004

    • Author(s)
      川口 浩
    • Journal Title

      日本臨床 63(増刊1)

      Pages: 676-679

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Zinc transporter 5 (Znt5) is an essential molecule for mechanical stress signaling in bone.2003

    • Author(s)
      Koichi Matsuda
    • Journal Title

      J Bone Miner Res 18

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 新規遺伝子Zent6(Zinc transporter 5)はメカニカルストレスに反応して骨量を維持する2003

    • Author(s)
      山川 聖史
    • Journal Title

      日本整形外科学会雑誌 77(8)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Zinc transporter 5 (Znt5) is an essential molecule for mechanical stress signaling in bone.2003

    • Author(s)
      Koichi Matsuda
    • Journal Title

      J Bone Miner Res. 18 : S

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Zinc transporter 5 (Znt5) maintains bone volume respond to mechanical stress signaling.2003

    • Author(s)
      Kiyofumi Yamakawa
    • Journal Title

      J.Jpn.Orthop.Assoc. 77(8) : S941

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] 川口 浩: "骨粗鬆症の分子生物学的病態"脊椎脊髄ジャーナル. 16・9. 919-926 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 篠田 裕介: "骨のremodellingに関する最近の話題"CLINICAL CALCIUM. 14・1. 70-74 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "加齢と骨"CLINICAL CALCIUM. 14・2. 275-283 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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