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Analysis and clinical application of new function of osteoprotegerin as anti-aging factor

Research Project

Project/Area Number 17K19776
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Oral Science and related fields
Research InstitutionMatsumoto Dental University

Principal Investigator

UDAGAWA NOBUYUKI  松本歯科大学, 歯学部, 教授 (70245801)

Co-Investigator(Kenkyū-buntansha) 小出 雅則  松本歯科大学, 総合歯科医学研究所, 准教授 (10367617)
吉成 伸夫  松本歯科大学, 歯学部, 教授 (20231699)
中本 哲自  朝日大学, 歯学部, 教授 (30514989)
中村 美どり  松本歯科大学, 歯学部, 准教授 (90278177)
上原 俊介  松本歯科大学, 歯学部, 講師 (90434480)
Project Period (FY) 2017-06-30 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywords骨代謝学 / 循環器学 / 骨粗鬆症 / 歯周病 / 抗加齢因子 / 骨カップリング / OPG / RANKL / 破骨細胞 / 骨芽細胞 / 骨代謝共役 / 心臓血管疾患 / 動脈硬化 / スクレロスチン / オステオプロテゲリン / 骨吸収 / 骨形成 / RANKL / OPG / 心臓肥大
Outline of Final Research Achievements

Osteoprotegerin (OPG) is expressed in cardiovascular system, and it may regulate not only bone metabolism but also contribute to the remodeling of heart and vasculature. We explored the roles of OPG in cardiovascular system using OPG-deficient mice. 1. OPG-deficient mice displayed the elevated systemic blood pressure, left ventricular hypertrophy with reduced contractility, compared with wild-type mice with age. Angiotensin II administration to the mice accelerated the heart failure. 2. Angiotensin II stimulation of OPG-deficient mice led to a high mortality due to aortic rupture. Histological analysis showed fragmentation of elastic fibers in the medial layer. We also analyzed the PCR arrays, and found the specific alteration of genes associated with extracellular matrix.
These results suggest that OPG may have protective roles to maintain the structural integrity against angiotensin II, and it may be a potential therapeutic target for heart failure and aortic dissection.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、骨代謝学と循環器学(心臓血管学)の融合を目指したOsteocardiology(骨循環器学)の構築に寄与するに繋がる。OPG欠損マウスにおいて認められる骨粗鬆化、血管石灰化、心臓肥大といった形質の連関を探ることにより、抗加齢因子としてのOPGの新しい役割を証明することに成功した。OPGの抗加齢因子としての新しい機能として、歯周病や骨粗鬆症のみならず、心臓血管疾患、糖尿病、肥満といった全身疾患の治療のツールとして応用することの糸口を得ることが出来た。この研究結果は、骨代謝研究が各種生活習慣病の治療戦略に寄与する可能性を秘めており、今後の更なる研究の進展が期待される。

Report

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

    (28 results)

All 2020 2019 2018 2017

All Journal Article (17 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 17 results,  Open Access: 11 results,  Acknowledgement Compliant: 1 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 4 results) Book (2 results)

  • [Journal Article] Osteoprotegerin-dependent Mcell self-regulation balances gut infection and immunity.2020

    • Author(s)
      Kimura S, Nakamura Y, Kobayashi N, Shiroguchi K, KawakamiE, Mutoh M, Takahashi-Iwanaga H, Yamada T, Hisamoto M, Nakamura M, Udagawa N, Sato S, KaishoT, Iwanaga T, Hase K.
    • Journal Title

      Nat Commun

      Volume: 11 Issue: 1 Pages: 234-234

    • DOI

      10.1038/s41467-019-13883-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of Small-molecule GSK3 Antagonist on Differentiation of Rat Dental Pulp Cells into Odontoblasts.2019

    • Author(s)
      Masuda Y, Sakagami H, Yokose S, Udagawa N
    • Journal Title

      In Vivo

      Volume: 61 Issue: 3 Pages: 135-140

    • DOI

      10.21873/invivo.11877

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of osteoclast function via Rho-Pkn3-c-Src pathways.2019

    • Author(s)
      Uehara S, Udagawa N, Kobayashi Y
    • Journal Title

      J Oral Biosci

      Volume: 61 Issue: 3 Pages: 135-140

    • DOI

      10.1016/j.job.2019.07.002

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of the angiotensin II type 1 receptor increases bone mineral density and left ventricular contractility in a mouse model of juvenile Paget disease.2019

    • Author(s)
      Tsuruda T, Funamoto T, Udagawa N, Kurogi S, Nakamichi Y, Koide M, Chosa E, Asada Y, Kitamura K
    • Journal Title

      Eur J Pharmacol

      Volume: 859 Pages: 172519-172519

    • DOI

      10.1016/j.ejphar.2019.172519

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Parathyroid Hormone Shifts Cell Fate of a Leptin Receptor-Marked Stromal Population from Adipogenic to Osteoblastic Lineage.2019

    • Author(s)
      Yang M, Arai A, Udagawa N, Zhao L, Nishida D, Murakami K, Hiraga T, Takao-Kawabata R, Matsuo K, Komori T, Kobayashi Y, Takahashi N, Isogai Y, Ishizuya T, Yamaguchi A, Mizoguchi T
    • Journal Title

      J Bone Miner Res

      Volume: 34 Issue: 10 Pages: 1952-1963

    • DOI

      10.1002/jbmr.3811

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 歯周組織の状態とフレイル,ソーシャルキャピタルの関連性に関する疫学研究.2019

    • Author(s)
      杉江美穂, 中村 卓, 中澤恵美子, 小町谷美帆, 田口 明, 宇田川信之, 吉成伸夫
    • Journal Title

      松本歯学

      Volume: 45 Pages: 1-10

    • NAID

      120006718418

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coupling of bone resorption and formation by RANKL reverse signalling.2018

    • Author(s)
      Ikebuchi Y, Aoki S, Honma M, Hayashi M, Sugamori Y, Khan M, Kariya Y, Kato G, Tabata Y, Penninger JM, Udagawa N, Aoki K, Suzuki H
    • Journal Title

      Nature

      Volume: 561 Issue: 7722 Pages: 195-200

    • DOI

      10.1038/s41586-018-0482-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Non-canonical Wnt signals regulate cytoskeletal remodeling in osteoclasts.2018

    • Author(s)
      Uehara S, Udagawa N, Kobayashi Y
    • Journal Title

      Cell Mol Life Sci

      Volume: 75 Issue: 20 Pages: 3683-3692

    • DOI

      10.1007/s00018-018-2881-1

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Olfactomedin-like protein OLFML1 inhibits Hippo signaling and mineralization in osteoblasts.2018

    • Author(s)
      Murakami K, Kikugawa S, Kobayashi Y, Uehara S, Suzuki T, Kato H, Udagawa N, Nakamura Y
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 28 Issue: 2 Pages: 419-425

    • DOI

      10.1016/j.bbrc.2018.09.112

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 歯周治療の動脈硬化症指標(Cardio Ankle Vascular Index: CAVI)に対する効果.2018

    • Author(s)
      守安攝子, 長岡 香, 中澤恵美子, 福満典子, 中村美どり, 荒 敏昭, 吉成伸夫, 宇田川信之, 矢ヶ﨑 雅
    • Journal Title

      松本歯学

      Volume: 44 Pages: 79-87

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [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 Research-status Report
    • Peer Reviewed / Open Access
  • [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 Research-status 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 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The W9 peptide directly stimulates osteoblast differentiation via RANKL signaling.2017

    • Author(s)
      Nakamura M, Nakamichi Y, Mizoguchi T, Koide M, Yamashita T, Ara T, Nakamura H, Penninger JM, Furuya Y, Yasuda H and Udagawa N
    • Journal Title

      Journal of Oral Biosciences

      Volume: 59 Pages: 146-151

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [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 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Importance of osteoclasts in osteogenic signals.2019

    • Author(s)
      Nobuyuki Udagawa, Masanori Koide, Teruhito Yamashita, Midori Nakamura, Shunsuke Uehara, Yasuhiro Kobayashi, Naoyuki Takahashi
    • Organizer
      日本分子生物学会年会(第42回)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Siglec-15中和抗体による骨吸収抑制作用と骨芽細胞分化促進作用2019

    • Author(s)
      宇田川信之,小出雅則,上原俊介,荒井敦,溝口利英,山下照仁,中村美どり,小林泰浩,高橋直之,熊倉誠一郎,福田千恵,津田英資
    • Organizer
      日本再生医療学会総会(第18回)
    • Related Report
      2019 Annual Research Report
  • [Presentation] Osteoclasts promote trabecular bone formation through the suppression of sclerostin expression.2019

    • Author(s)
      Masanori Koide, Yasuhiro Kobayashi, Teruhito Yamashita, Kohei Murakami, Shunsuke Uehara, Hisataka Yasuda, Naoyuki Takahashi, Nobuyuki Udagawa
    • Organizer
      The American Society for Bone and Mineral Research (ASBMR) 2019 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Histochemical evidence of the presence of osteoclast-like cells in RANKL-/- mice.2019

    • Author(s)
      Yukina Miyamoto Takasaki, Miki Abe, Norio Amizuka, Tomoka Hasegawa, Nobuyuki Udagawa
    • Organizer
      The American Society for Bone and Mineral Research (ASBMR) 2019 Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 臓器年齢と酸化ストレス-破骨細胞研究からの骨年齢-2018

    • Author(s)
      宇田川信之
    • Organizer
      日本抗加齢学会総会 (第18回)
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 骨はダイナミックに躍動している2018

    • Author(s)
      宇田川信之
    • Organizer
      日本歯科理工学会中部地方会夏期セミナー
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 骨改造制御の新局面:骨吸収から骨形成・骨再生への橋渡し機構を探る-破骨細胞の骨形成シグナルにおける重要性-2018

    • Author(s)
      宇田川信之
    • Organizer
      歯科基礎医学会学術大会(第60回)
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] 歯槽骨の骨リモデリングにおける骨細胞の役割2018

    • Author(s)
      小出雅則, 宇田川信之
    • Organizer
      日本骨代謝学会学術集会 (第36回)
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) plays important roles in the induction of both bone-resorbing activity of osteoclasts and osteoblast differentiation.2018

    • Author(s)
      Udagawa N, Koide M, Uehara S, Arai A, Mizoguchi T, Yamashita T, Nakamura M, Kobayashi Y, Takahashi N, Kumakura S, Fukuda C, Tsuda E
    • Organizer
      The American Society for Bone and Mineral Research (ASBMR) 2018 Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Book] Osteoclasts. Principles of Bone Biology 4th Edition2019

    • Author(s)
      Takahashi N, Kobayashi Y, Udagawa N
    • Total Pages
      2024
    • Publisher
      Elsevier Academic Press
    • Related Report
      2019 Annual Research Report
  • [Book] 高齢者への歯周治療と口腔管理2018

    • Author(s)
      宇田川信之,小出雅則,中村美どり, 尾崎友輝, 吉成伸夫
    • Total Pages
      283
    • Publisher
      インターアクション社
    • ISBN
      9784909066053
    • Related Report
      2018 Research-status Report

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Published: 2017-07-21   Modified: 2021-02-19  

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