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Inflammatory and necrotic effects of nitrogen-containing bisphosphonates: involvement of phosphate transporters

Research Project

Project/Area Number 16K11672
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Surgical dentistry
Research InstitutionTohoku University

Principal Investigator

Endo Yasuo  東北大学, 歯学研究科, 学術研究員 (50005039)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsbisphosphonate / 炎症 / 顎骨壊死 / etidronate / clodronate / 鎮痛作用 / 副作用 / LPS / IL-1 / bisphosphonte / 骨吸収抑制薬 / リン酸トランスポーター
Outline of Final Research Achievements

Bisphosphonates (BPs) are widely used anti-bone-resorptive drugs. Among them, the anti-bone-resorptive effects of nitrogen-containing BPs (NBPs) are much stronger than those of non-NBPs. However, NBPs have inflammatory/necrotic side effects, and the osteonecrosis of the jaw induced by NBPs is intractable and serious problem in dentistry. The present study, together with previous studies, demonstrtates that NBPs enter soft-tissue cells via phosphate transporters and non-NBPs inhibit this. These findings suggest that non-NBPs are applicable to treat and prevent the side effects of NBPs. In addition, we found that non-NBPs exhibit analgesic effects, too, via inhibition of neuronal phosphate transporters.

Academic Significance and Societal Importance of the Research Achievements

骨粗鬆症は高齢者の生活低下の大きな原因である.窒素含有bisphosphonates (NBPs) は現在,骨粗鬆症の予防・治療の第一選択薬であり,宇宙での無重力による骨粗鬆の予防薬にも期待されている.しかし残念ながら,NBPsの副作用 (顎骨壊死や発熱などの急性炎症) が大きな問題となっており,その安全な利用法の確立は急務の課題である.臨床成績も含めて私達の研究成果は,NBPsの副作用に対する予防・治療薬として,non-NBPの etidronateとclodronateの有効性を明確に示している.いくつかの方法が報告されているが,有効性は低く,私たちの提案する方法が最善と思われる.

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (17 results)

All 2020 2019 2018 2017 2016

All Journal Article (15 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 14 results,  Open Access: 13 results,  Acknowledgement Compliant: 2 results) Presentation (2 results)

  • [Journal Article] Basic Studies on the Mechanism, Prevention, and Treatment of Osteonecrosis of the Jaw Induced by Bisphosphonates2020

    • Author(s)
      Endo Yasuo、Funayama Hiromi、Yamaguchi Kouji、Monma Yuko、Yu Zhiqian、Deng Xue、Oizumi Takefumi、Shikama Yosuke、Tanaka Yukinori、Okada Satoshi、Kim Siyoung、Kiyama Tomomi、Bando Kanan、Shima Kazuhiro、Suzuki Hikari、Takahashi Tetsu
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 140 Issue: 1 Pages: 63-79

    • DOI

      10.1248/yakushi.19-00125

    • NAID

      130007778763

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2020-01-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Augmentation of Lipopolysaccharide-Induced Production of IL-1α and IL-1β in Mice Given Intravenous Zoledronate (a Nitrogen-Containing Bisphosphonate) and Its Prevention by Clodronate (a Non-nitrogen-containing Bisphosphonate)2019

    • Author(s)
      Suzuki H, Bando K, Tada H, Kiyama T, Oizumi T, Funayama H, Sugawara S, Takahashi T, Endo Y.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 2 Pages: 164-172

    • DOI

      10.1248/bpb.b18-00408

    • NAID

      130007588866

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-02-01
    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 造血組織と骨:ビスフォスフォネートの関与(総説).2019

    • Author(s)
      中村雅典,八木秀樹,大塚裕忠,遠藤康男.
    • Journal Title

      炎症と免疫

      Volume: 27 Pages: 463-468

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Dynamics of platelet behaviors as defenders and guardians: accumulations in liver, lung, and spleen in mice.2019

    • Author(s)
      Zhiqian Yu, Masahiro Shibazaki, Hirotada Otsuka, Haruhiko Takada, Masanori Nakamura, Yasuo Endo.
    • Journal Title

      Biol Pharm Bull

      Volume: in press

    • NAID

      130007686671

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Etidronate attenuates tactile allodynia by spinal ATP release inhibition in mice with partial sciatic nerve ligation2018

    • Author(s)
      Yamagata Ryota、Nemoto Wataru、Nakagawasai Osamu、Hung Wan-Yi、Shima Kazuhiro、Endo Yasuo、Tan-No Koichi
    • Journal Title

      Naunyn-Schmiedeberg's Archives of Pharmacology

      Volume: 392 Issue: 3 Pages: 349-357

    • DOI

      10.1007/s00210-018-1593-2

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain2017

    • Author(s)
      Kato Yuri、Hiasa Miki、Ichikawa Reiko、Hasuzawa Nao、Kadowaki Atsushi、Iwatsuki Ken、Shima Kazuhiro、Endo Yasuo、Kitahara Yoshiro、Inoue Tsuyoshi、Nomura Masatoshi、Omote Hiroshi、Moriyama Yoshinori、Miyaji Takaaki
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 114 Issue: 31

    • DOI

      10.1073/pnas.1704847114

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Underlying Mechanisms and Therapeutic Strategies for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)2017

    • Author(s)
      Endo Y, Kumamoto H, Nakamura M, Sugawara S, Takano-Yamamoto T, Sasaki K, Takahashi T
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 6 Pages: 739-750

    • DOI

      10.1248/bpb.b16-01020

    • NAID

      130005688081

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs2017

    • Author(s)
      Shima K, Tsuchiya M, Oizumi T, Takano-Yamamoto T, Sugawara S, Endo Y.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 1 Pages: 25-33

    • DOI

      10.1248/bpb.b16-00521

    • NAID

      130005188786

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pulmonary platelet accumulation induced by catecholamines: its nvolvement in lipopolysaccharide-induced anaphylaxis-like shock.2017

    • Author(s)
      Zhiqian Yu, Hiroko Saito, Hirotada Otsuka, Yosuke Shikama, Hiromi Funayama, Mai Sakai, Shigeo Murai, Masanori Nakamura, Takashi Yokochi, Haruhiko Takada, Shunji Sugawara, Yasuo Endo.
    • Journal Title

      International Immunopharmacol

      Volume: 43 Pages: 40-53

    • DOI

      10.1016/j.intimp.2016.11.034

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ビスフォスフォネート関連顎骨壊死(BRONJ)のエチドロネート代用置換治療の試み:糖尿病患者での症例.2016

    • Author(s)
      大泉丈史,長坂浩,高橋正任,山口晃史,遠藤康男,高橋哲.
    • Journal Title

      東北大学歯学雑誌

      Volume: 34/35 Pages: 66-72

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] A Strategy against the Osteonecrosis of the Jaw Associated with Nitrogen-Containing Bisphosphonates (N-BPs): Attempts to Replace N-BPs with the Non-N-BP Etidronate2016

    • Author(s)
      Oizumi T, Yamaguchi K, Sato K, Okada S, Suzuki H, Funayama H, Mori S, Nagasaka H, Tsuchiya M, Hagiwara W, Itoi E, Sugawara S, Takahashi T, Endo Y:
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 9 Pages: 1549-1554

    • DOI

      10.1248/bpb.b16-00041

    • NAID

      130005262320

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Bisphosphonates Clodronate and Etidronate Exert Analgesic Effects by Acting on Glutamate- and/or ATP-Related Pain Transmission Pathways2016

    • Author(s)
      Shima K, Nemoto W, Tsuchiya M, Tan-No K, Takano-Yamamoto T, Sugawara S, Endo Y.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 5 Pages: 770-777

    • DOI

      10.1248/bpb.b15-00882

    • NAID

      130005149271

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters2016

    • Author(s)
      Kiyama T, Tsuchiya M, Okada S, Oizumi T, Yamaguchi K, Sasaki K, Sugawara S, Endo Y.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 5 Pages: 712-720

    • DOI

      10.1248/bpb.b15-00770

    • NAID

      130005149275

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mast cell histamine-mediated transient inflammation following exposure to nickel promotes nickel allergy in mice2016

    • Author(s)
      Kinbara M, Bando K, Shiraishi D, Kuroishi T, Nagai Y, Ohtsu H, Takano-Yamamoto T, Sugawara S, Endo Y
    • Journal Title

      Exp Dermatol.

      Volume: 印刷中 Issue: 6 Pages: 466-71

    • DOI

      10.1111/exd.12985

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Analgesic Effects of 1st Generation Anti-histamines in Mice2016

    • Author(s)
      Mebae Takahashi, Kazuhiro Shima, Masahiro Tsuchiya, Yoshihiro Hagiwara, Hirokazu Mizoguchi, Shinobu Sakurada, Shunji Sugawara, Takuo Fujita, Takeshi Tadano, Makoto Watanabe, Satoshi Fukumoto, Yasuo Endo
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 39 Issue: 4 Pages: 620-624

    • DOI

      10.1248/bpb.b15-00755

    • NAID

      130005141684

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ハイドロキシアパタイト (HA) に結合した窒素含有bisphosphonates (N-BPs) のnon-N-BPs (etidronateおよびclodronate) による遊離.2020

    • Author(s)
      大泉丈史 他.
    • Organizer
      東北骨代謝・骨粗鬆症研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ゾルドロネート静脈投与マウスでの LPS による IL-1αおよび IL-1β の産生増強とクロドロネートによる抑制.2019

    • Author(s)
      鈴木飛佳理 他.
    • Organizer
      口腔外科学会
    • Related Report
      2019 Annual Research Report

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Published: 2016-04-21   Modified: 2021-02-19  

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