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Regulation of bone formation and osteocyte function by nuclear protein involved in sclerostin regulation

Research Project

Project/Area Number 19K09553
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionSaga University

Principal Investigator

Mawatari Masaaki  佐賀大学, 医学部, 教授 (80202357)

Co-Investigator(Kenkyū-buntansha) 久木田 明子  佐賀大学, 医学部, 寄附講座教授 (30153266)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords骨代謝 / 骨細胞 / 転写制御因子 / 骨粗鬆症 / 骨形成 / 骨芽細胞 / 細胞骨格 / スクレロスチン / 核蛋白質
Outline of Research at the Start

健康な骨を維持するためには、骨代謝を司る3つの主要な細胞である破骨細胞、骨芽細胞と骨細胞の機能とそのバランスが重要な役割を持っている。骨細胞は骨芽細胞が最終分化した細胞で骨全体にネットワークを形成し、スクレロスチンを介した骨形成抑制や骨吸収制御にも関わっている。核蛋白質Nupr1は骨細胞で高く発現し、骨芽細胞のオートファージーや骨芽細胞や骨細胞の機能制御に関わることが分かってきた。本研究ではNupr1によるスクレロスチンや骨細胞の機能制御及びNupr1の遺伝子欠損マウスを用いた病態モデルの解析やヒト骨疾患との関連性を解析し、新たな病態の評価系や治療法開発の研究に繋げる。

Outline of Final Research Achievements

We analyzed the role of transcriptional regulator Nupr1 in osteocytes and osteoblasts. Nupr1 was highly expressed in osteocytes and osteoblasts expressing screrostin. Nupr1 overexpression promoted screrostin expression, and the expression of Wnt signaling molecules was reduced in osteoblasts derived from Nupr1 knockout mice. In addition, expression of cytoskeleton proteins, its regulatory proteins, and proteases which are thought to be involved in bone formation, was decreased in osteocytes derived from Nupr1 knockout mice. The results suggest that Nupr1 is involved in bone formation by regulating the function of osteocytes through the control of cytoskeleton organization and protease production.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に伴い、骨粗鬆症などの骨・関節疾患の患者数が増加し、重大な社会問題となっている。近年、骨吸収を行う破骨細胞と骨形成を行う骨芽細胞に加えて、骨の中に最も多く存在し、神経細胞のようなネットワークを形成する骨細胞が骨代謝や骨のホメオスタシスに重要な役割を持つことが考えられている。本研究では、マウスで遺伝子を欠損すると骨形成が亢進するNupr1という転写制御因子の骨芽細胞と骨細胞での発現とNupr1による骨形成の新たな制御機構を明らかにした。本研究の結果は、骨粗鬆症や変形性関節症などの骨・関節疾患の病態の解明や新たな治療法の開発などに将来的に寄与するものと考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (16 results)

All 2022 2021 2020 2019

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results) Presentation (10 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] LRF/OCZF overexpression promotes osteoclast survival by increasing Bcl-xl mRNA: a novel regulatory mechanism mediated by RNA binding protein SAM682022

    • Author(s)
      Xianghe Xu, Takeo Shobuike, Makoto Shiraki, Asana Kamohara, Hirohito Hirata, Masatoshi Murayama, Daisuke Mawatari3, Masaya Ueno3, Tadatsugu Morimoto, Toshio Kukita, Masaaki Mawatari, Akiko Kukita1
    • Journal Title

      Lab. Invest.

      Volume: -

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PMEPA1 and NEDD4 control proton production of osteoclasts by regulating vesicular trafficking2021

    • Author(s)
      75.Hirata H, Xu X, Nishioka K, Matsuhisa F, Kitajima S, Kukita T, Murayama M, Urano Y, Miyamoto H, Mawatari M, Kukita A
    • Journal Title

      FASEB J.

      Volume: 35 Issue: 2

    • DOI

      10.1096/fj.202001795r

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2.2020

    • Author(s)
      Kamohara A, Hirata H, Xu X, Shiraki M, Yamada S, Zhang JQ, Kukita T, Toyonaga K, Hara H, Urano Y, Yamashita Y, Miyamoto H, Kukita A.
    • Journal Title

      Int Immunol. 2020 Feb 7;32(2):89-104.

      Volume: 32 Issue: 2 Pages: 89-104

    • DOI

      10.1093/intimm/dxz063

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts.2019

    • Author(s)
      Shiraki M, Xu X, Iovanna JL, Kukita T, Hirata H, Kamohara A, Kubota Y, Miyamoto H, Mawatari M, Kukita A.
    • Journal Title

      FASEB J.

      Volume: 33 Issue: 8 Pages: 8836-8852

    • DOI

      10.1096/fj.201802322rr

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption2019

    • Author(s)
      Xu Xianghe、Hirata Hirohito、Shiraki Makoto、Kamohara Asana、Nishioka Kenichi、Miyamoto Hiroshi、Kukita Toshio、Kukita Akiko
    • Journal Title

      The FASEB Journal

      Volume: 33 Issue: 3 Pages: 4365-4375

    • DOI

      10.1096/fj.201801573r

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Antibacterial Activity of Ag-Hydroxyapatite Coating Against Hematogenous Infection by Methicillin-Resistant Staphylococcus aureus in the Rat Femur.2019

    • Author(s)
      Kobatake T, Miyamoto H, Hashimoto A, Ueno M, Nakashima T, Murakami T, Noda I, Shobuike T, Sonohata M, Mawatari M.
    • Journal Title

      J Orthop Res.

      Volume: 12 Issue: 12 Pages: 2655-2660

    • DOI

      10.1002/jor.24431

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Nupr1は加齢による骨量減少と老化関連遺伝子発現に関与する2021

    • Author(s)
      村山雅俊、平田寛人、馬渡正明、久木田明子
    • Organizer
      第23回日本骨粗鬆症学会・第39回日本骨代謝学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] shRNAライブラリースクリーニングによる新たな破骨細胞骨吸収制御因子の網羅的探索とその候補遺伝子の作用機構の解析2021

    • Author(s)
      平田寛人、蒲原麻菜、村山雅俊、馬渡正明、久木田明子
    • Organizer
      第23回日本骨粗鬆症学会・第39回日本骨代謝学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Nupr1はマウスモデルで加齢による骨量減少と老化関連遺伝子発現に関与する2021

    • Author(s)
      村山雅俊、平田寛人、久木田明子、馬渡正明
    • Organizer
      第36回日本整形外科学会基礎学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Pmepa1は小胞輸送に関わり骨吸収中の破骨細胞で酸の分泌を制御する2020

    • Author(s)
      平田寛人、村山雅俊、白木誠、久木田敏夫、馬渡正明、久木田明子
    • Organizer
      第38回 日本骨代謝学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Pmepa1は骨吸収中の破骨細胞で小胞輸送に関わり酸の分泌を制御する2020

    • Author(s)
      平田寛人,村山雅俊,白木誠,久木田敏夫,久木田明子,馬渡正明
    • Organizer
      第35回 日本整形外科学会基礎学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Prostate transmembrane protein androgen induced-1 and Nedd4 Regulate Bone Resorption by Promoting Proton Production in Osteoclasts2020

    • Author(s)
      Hirohito Hirata, Xianghe Xu, Masatoshi Murayama, Makoto Shiraki, Toshio Kukita, Mawatari Masaaki, Akiko Kukita
    • Organizer
      The ASBMR 2021 Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 1型膜蛋白質Pmepa1は骨吸収を制御し、破骨細胞でNedd4と共局在する2019

    • Author(s)
      平田 寛人、久木田明子、白木誠、 蒲原 麻菜、園畑素樹、 馬渡 正明
    • Organizer
      第34回日本整形外科学会基礎学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Pmepa1は破骨細胞でNedd4とLAMP2と共局在し骨吸収を制御する2019

    • Author(s)
      平田寛人、徐祥赫、白木誠、蒲原麻菜、久木田敏夫、馬渡正明、久木田明子
    • Organizer
      第37回 日本骨代謝学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Deficiency of stress-associated gene Nupr1/p8 increased bone volume by enhancing differentiation of osteoblasts2019

    • Author(s)
      Shiraki M, Xu X, Iovanna JL, Kukita T, Hirata H, Kamohara A, Kubota Y, Miyamoto H, Mawatari M, Kukita A.
    • Organizer
      第42回 日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Prostate transmembrane protein androgen induced-1 is localized to lysosome with Nedd4 in osteoclasts, and regulates bone resorption2019

    • Author(s)
      H.Hirata, X. Xu, M. Shiraki, M. Murayama, A. Kamohara, K. Nishioka, F. Matsuhisa, S. Kitajima, Y. Urano, H. Miyamoto, T. Kukita, M. Mawatari, A. Kukita
    • Organizer
      第42回 日本分子生物学会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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