• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Elucidation of the osteoclast-derived cytokine-Wnt signaling network responsible for coupling between bone resorption and formation.

Research Project

Project/Area Number 16H05144
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionMatsumoto Dental University

Principal Investigator

Takahashi Naoyuki  松本歯科大学, 総合歯科医学研究所, 特任教授 (90119222)

Co-Investigator(Kenkyū-buntansha) 宇田川 信之  松本歯科大学, 歯学部, 教授 (70245801)
小林 泰浩  松本歯科大学, 総合歯科医学研究所, 教授 (20264252)
中村 浩彰  松本歯科大学, 歯学部, 教授 (50227930)
南 康博  神戸大学, 医学研究科, 教授 (70229772)
荒 敏昭  松本歯科大学, 歯学部, 講師 (90387423)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2016: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords破骨細胞 / 骨芽細胞 / カップリング因子 / クラストカイン / スクレロスチン / LIF / HtrA1 / Wnt5a / 骨代謝共役 / Wntシグナル
Outline of Final Research Achievements

Clastokines secreted by osteoclasts were analyzed. (1) Osteoclasts secreted LIF, which suppressed the secretion of sclerostin by osteocytes. Thus, osteoclasts promoted osteoblastic bone formation through the up-regulation of Wnt-βcatenin signals. (2) W9 peptides suppressed bone resorption activity of osteoclasts and suppressed sclerostin expression by osteocytes. Thus, W9 increased the alveolar bone mass. (3) Osteoclasts abundantly secreted Wnt5a. Wnt5a binds to its receptor, Ror2, which is expressed by osteoclasts. The Wnt5a-Ror2 signal in osteoclasts induced bone-resorbing activity through Daam2→ Rho→ PKN3→ cSrc/Pyk2 signals. (4) Osteoclasts specifically secreted HtrA1, which degraded OPG, suggesting that osteoclasts potentially prepare a microenvironment that is suitable for osteoclastogenesis. Thus, osteoclasts secrete various Clastokines that are involved in bone metabolism.

Academic Significance and Societal Importance of the Research Achievements

従来破骨細胞は骨吸収のみを行う細胞であると考えられてきた。しかし本研究より、破骨細胞は様々なクラストカインを分泌し、骨代謝とりわけ骨代謝共役を担っていることが示された。本研究成果は、破骨細胞がサイトカイン分泌細胞であるあるいは内分泌細胞であるという新しい考え方を示すことができたと考える。さらにLIFの作用を抑制する薬剤、W9ペプチド、HtrA1の阻害剤は特粗鬆症など代謝性骨疾患の治療薬となり得る可能性が示された。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (21 results)

All 2019 2018 2017 2016 2015

All Journal Article (12 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 12 results,  Open Access: 12 results,  Acknowledgement Compliant: 2 results) Presentation (9 results) (of which Invited: 7 results)

  • [Journal Article] Murine osteoclasts secrete serine protease HtrA1 capable of degrading osteoprotegerin in the bone microenvironment2019

    • Author(s)
      Ochiai Nagahiro、Nakachi Yutaka、Yokoo Tomotaka、Ichihara Takahiro、Eriksson Tore、Yonemoto Yuki、Kato Takehiko、Ogata Hitoshi、Fujimoto Natsuko、Kobayashi Yasuhiro、Udagawa Nobuyuki、Kaku Shinsuke、Ueki Tomokazu、Okazaki Yasushi、Takahashi Naoyuki、Suda Tatsuo
    • Journal Title

      Communications Biology

      Volume: 2 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s42003-019-0334-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mechanisms involved in bone resorption regulated by vitamin D2018

    • Author(s)
      Nakamichi Yuko、Udagawa Nobuyuki、Suda Tatsuo、Takahashi Naoyuki
    • Journal Title

      The Journal of Steroid Biochemistry and Molecular Biology

      Volume: 177 Pages: 70-76

    • DOI

      10.1016/j.jsbmb.2017.11.005

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment of OPG-deficient mice with WP9QY, a RANKL-binding peptide, recovers alveolar bone loss by suppressing osteoclastogenesis and enhancing osteoblastogenesis2017

    • Author(s)
      Ozaki Yuki、Koide Masanori、Furuya Yuriko、Ninomiya Tadashi、Yasuda Hisataka、Nakamura Midori、Kobayashi Yasuhiro、Takahashi Naoyuki、Yoshinari Nobuo、Udagawa Nobuyuki
    • Journal Title

      PLOS ONE

      Volume: 12 Issue: 9 Pages: e0184904-e0184904

    • DOI

      10.1371/journal.pone.0184904

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Protein kinase N3 promotes bone resorption by osteoclasts in response to Wnt5a-Ror2 signaling.2017

    • Author(s)
      Uehara S, Udagawa N, Mukai H, Ishihara A, Maeda K, Yamashita T, Murakami K, Nishita M, Nakamura T, Kato S, Minami Y, Takahashi N and Kobayashi Y
    • Journal Title

      Sci Signal

      Volume: 10 Issue: 494

    • DOI

      10.1126/scisignal.aan0023

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro.2017

    • Author(s)
      Murakami K, Kobayashi Y, Uehara S, Suzuki T, Koide M, Yamashita T, Nakamura M, Takahashi N, Kato H, Udagawa N and Nakamura Y
    • Journal Title

      PLOS ONE

      Volume: 12 Issue: 7 Pages: e0181126-e0181126

    • DOI

      10.1371/journal.pone.0181126

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Osteogenic Factor Runx2 Marks a Subset of Leptin Receptor-Positive Cells that Sit Atop the Bone Marrow Stromal Cell Hierarchy2017

    • Author(s)
      Yang Mengyu、Arai Atsushi、Udagawa Nobuyuki、Hiraga Toru、Lijuan Zhao、Ito Susumu、Komori Toshihisa、Moriishi Takeshi、Matsuo Koichi、Shimoda Kouji、Zahalka Ali H.、Kobayashi Yasuhiro、Takahashi Naoyuki、Mizoguchi Toshihide
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 4928-4928

    • DOI

      10.1038/s41598-017-05401-1

    • NAID

      120006576162

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bone Formation is coupled to resorption via suppression of sclerostin expression by osteoclasts.2017

    • Author(s)
      Koide M, Kobayashi Y, Yamashita T, Uehara S, Nakamura M, Hiraoka BY, Ozaki Y, Iimura T, Yasuda H, Takahashi N and Udagawa N
    • Journal Title

      J Bone Mineral Res

      Volume: 32 Issue: 10 Pages: 2074-2086

    • DOI

      10.1002/jbmr.3175

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] VDR in osteoblast-lineage cells primarily mediates vitamin D treatment-iInduced increase in bone mass by suppressing bone resorption.2017

    • Author(s)
      Nakamichi Y, Udagawa N, Horibe K, Mizoguchi T, Yamamoto Y, Nakamura T, Hosoya A, Kato S, Suda T, Takahashi N
    • Journal Title

      J Bone Miner Res

      Volume: 32 Issue: 6 Pages: 1297-1308

    • DOI

      10.1002/jbmr.3096

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Platypus and opossum calcitonins exhibit strong activities, even though they belong to mammals.2017

    • Author(s)
      Yamashita T, Udagawa N, Thirukonda GJ, Uehara S, Yamauchi H, Suzuki N, Li F, Kobayashi Y, Takahashi N.
    • Journal Title

      Gen Comp Endocrinol.

      Volume: 246 Pages: 270-278

    • DOI

      10.1016/j.ygcen.2017.01.001

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts.2016

    • Author(s)
      Thirukonda GJ, Uehara S, Nakayama T, Yamashita T, Nakamura Y, Mizoguchi T, Takahashi N, Yagami K, Udagawa N, Kobayashi Y.
    • Journal Title

      J Bone Miner Metab

      Volume: 34 Issue: 4 Pages: 395-405

    • DOI

      10.1007/s00774-015-0683-1

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Platypus and opossum calcitonins exhibit strong activities, even though they belong to mammals.2016

    • Author(s)
      Yamashita T, Udagawa N, Thirukonda GJ, Uehara S, Yamauchi H, Suzuki N, Li F, Kobayashi Y, Takahashi N
    • Journal Title

      Gen Comp Endocrinol

      Volume: 246 Pages: 270-278

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The regulation of osteoclast differentiation by Wnt signals2015

    • Author(s)
      Kobayashi Y, Uehara S, Koide M, Takahashi N
    • Journal Title

      Bonekey Rep

      Volume: 4 Issue: 4 Pages: 713-713

    • DOI

      10.1093/jb/mvv124

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 破骨細胞生物学の歴史:RANKL発見までを振り返る。2019

    • Author(s)
      高橋直之
    • Organizer
      松本歯科大学総合歯科医学研究所開設30年記念講演会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 破骨細胞研究の歴史を振り返る2018

    • Author(s)
      高橋直之
    • Organizer
      第36回日本骨代謝学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] How does vitamin D regulate osteoclastic bone resorption?2018

    • Author(s)
      Naoyuki Takahashi
    • Organizer
      17th Annual Meeting of Korean Association of Oral Science
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] なぜ共存培養だったのか.2018

    • Author(s)
      高橋直之
    • Organizer
      2018 Dentistry Quo Vadis?
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Progress of osteoclast biology2017

    • Author(s)
      高橋直之
    • Organizer
      第2回日本骨免疫学会ウィンターセミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 須田先生と骨代謝研究2017

    • Author(s)
      高橋直之
    • Organizer
      第35回日本骨代謝学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] デノスマブが骨代謝研究に与えた影響2017

    • Author(s)
      高橋直之
    • Organizer
      2017年Dentistry, Quo Vadis?
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Wnt5a-Ror2シグナルにより活性化されるRor-Pkn3経路はc-Srcを介して骨吸収を調節する。2016

    • Author(s)
      上原俊介、山下照仁、中村 貴、加藤茂明、宇田川信之、高橋直之、小林泰浩
    • Organizer
      第34回日本骨代謝学会
    • Place of Presentation
      大阪国際会議場、大阪市北区中之島
    • Year and Date
      2016-07-21
    • Related Report
      2016 Annual Research Report
  • [Presentation] ビタミンDの骨量増加の薬理作用は、破骨細胞ではなく骨芽細胞のVDRを介する2016

    • Author(s)
      中道裕子、溝口利英、山本陽子、中村 貴、細矢明宏、堀部寛治、原田 卓、斎藤一史
    • Organizer
      第34回日本骨代謝学会
    • Place of Presentation
      大阪国際会議場、大阪市北区中之島
    • Year and Date
      2016-07-21
    • Related Report
      2016 Annual Research Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi