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Development of New Hybrid-type Drugs Targeted to the Mechanism of Bone Remodeling

Research Project

Project/Area Number 16209053
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionTokyo Medical and Dental University

Principal Investigator

OHYA Keiichi  Tokyo Medical and Dental University, Graduate School, Hard Tissue Engineering/Pharmacology, Professor, 大学院医歯学総合研究科, 教授 (10126211)

Co-Investigator(Kenkyū-buntansha) SHIMOKAWA Hitoyata  Tokyo Medical and Dental University, Graduate School, Hard Tissue Engineering/Pharmacology, Associate Professor, 大学院医歯学総合研究科, 助教授 (80014257)
AOKI Kazuhiro  Tokyo Medical and Dental University, Graduate School, Hard Tissue Engineering/Pharmacology, Assistant, 大学院医歯学総合研究科, 助手 (40272603)
TAKAHASHI Mariko  Tokyo Medical and Dental University, Faculty of Dentistry, Academic Staff, 歯学部, 教務職員 (90334440)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥48,620,000 (Direct Cost: ¥37,400,000、Indirect Cost: ¥11,220,000)
Fiscal Year 2006: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2005: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2004: ¥28,340,000 (Direct Cost: ¥21,800,000、Indirect Cost: ¥6,540,000)
Keywordsbone resorption / periodontitis / osteoclasts / Rheumatoid Arthritis / TNF / RANKL / Nano-gel / Mini-pump / RANK / NF-kβ / 骨粗鬆症
Research Abstract

The aim of this study is to develop newly drug molecules that act as bone resorption inhibitors and to make hybrid type drugs with new molecules and the pre-existed drugs or the delivery materials. The following results were obtained.
・The newly developed small peptide, WP9QY, is the antagonist for the TNF-a receptor and shows the activity to inhibit osteoclast formation. WP9QY also inhibit enhanced bone resorption in the animal model such as the low calcium feeding rats, the ovaryectomy rats, the arthritis induced rats and the periodontitis bacteria injected rats. In addition, WP9QY has the anti-inflammatory effects.
・Other than the antagonist for TNF-a receptor, WP9QY prevents the RANK-RANKL interaction and acts as an antagonist. WP9QY interferes the RANK-RANKL through its binding to the receptor-ligand complex and changing the conformation of the complex.
・Newly synthesized peptide, NBD, blocks the movement of NF-kB to the nucleus and interferes the proliferation and differentiation of osteoclasts. It also shows the inhibitory effects on bone resorption in various animal model for bone resorption.
・The hybrid molecule combined with CHP-nanogel and WP9QY peptide improves the stability of the peptide in the body and releases peptide slowly. The hybrid molecule inhibited bone resorption more efficiently than peptide itself in various animal model for bone resorption.
Form these results, the new drugs that target the cytokine receptor or the signal transduction system in osteoclasts seems to contribute the development of therapeutic regimen for bone resorption inhibitors. Moreover the hybrid molecules with hydrogel scaffolds and new drugs improve the stability and efficacy of drugs and these hybrid molecules may serve as a more potent drugs that inhibit bone resorption.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (22 results)

All 2007 2006 2005 2004 Other

All Journal Article (22 results)

  • [Journal Article] A Tumor Necrosis Factor Receptor Loop Peptide Mimic Inhibits Bone Destruction To The Same Extent as Anti-Tumor Necrosis Factor Monoclonal Antibody In Murine Collagen-Induced Arthritis.2007

    • Author(s)
      Saito H.
    • Journal Title

      Arthritis and rheumatism. 56(4)

      Pages: 1164-1174

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A Tumor Necrosis Factor Receptor Loop Peptide Mimic Inhibits Bone Destruction To The Same Extent as Anti-Tumor Necrosis Factor Monoclonal Antibody In Murine Collagen-Induced Arthritis.2007

    • Author(s)
      Saito H
    • Journal Title

      Arthritis and rheumatism 56(4)

      Pages: 1164-1174

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A Tumor Necrosis Factor Receptor Loop Peptide Mimic Inhibits Bone Destruction To The Same Extent as Anti-Tumor Necrosis Factor Monoclonal Antibody In Murine Collagen-Induced Arthritis.2007

    • Author(s)
      Saito H
    • Journal Title

      Arthritis and rheumatism. 56(4)

      Pages: 1164-1174

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss.2006

    • Author(s)
      Aoki K.
    • Journal Title

      The Journal of Clinical Investigation. 116(6)

      Pages: 1525-1534

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Three-Dimensional Measurements of Bone Resorption Lacunae Reveal Inhibition of Osteoclast Activity by TNF-α Antagonist In Vitro.2006

    • Author(s)
      Saito H.
    • Journal Title

      Dentistry in Japan. 42

      Pages: 35-37

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A tumor necrosis factor-α antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalis infection in mice.2006

    • Author(s)
      Suzuki Y.
    • Journal Title

      Journal of Periodontal Research. 41(2)

      Pages: 81-91

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss.2006

    • Author(s)
      Aoki K
    • Journal Title

      The Journal of Clinical Investigation 116(6)

      Pages: 1525-1534

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Three-Dimensional Measurements of Bone Resorption Lacunae Reveal Inhibition of Osteoclast Activity by TNF-α Antagonist In Vitro.2006

    • Author(s)
      Saito H
    • Journal Title

      Dentistry in Japan 42

      Pages: 35-37

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A tumor necrosis factor-α antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalis infection in mice.2006

    • Author(s)
      Suzuki Y
    • Journal Title

      Journal of Periodontal Research 41(2)

      Pages: 81-91

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A TNF receptor loop peptide mimic blocks RANK liganda-induces signaling, bone resorption, and bone loss.2006

    • Author(s)
      Aoki K.
    • Journal Title

      The Journal of Clinical Investigation. 116(6)

      Pages: 1525-1534

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Three-Dimensional measurements of Bone Resorption Lacunae Reveal Inhibition of Osteoclast Activity by TNF-α Antagonist In Vitro.2006

    • Author(s)
      Saito H
    • Journal Title

      Dentistry in Japan 42

      Pages: 35-37

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A tumor necrosis factor-α antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingival is infection in mice.2006

    • Author(s)
      Suzuki Y.
    • Journal Title

      Journal of Periodontal Research. 41(2)

      Pages: 81-91

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Three-Dimensional Measurements of Bone Resorption Lacunae Reveal Inhibition of Osteoclast Activity by TNF-α Antagonist In Vitro.2006

    • Author(s)
      Saito H, Soysa N, Alles N, Aoki K, Ohya K.
    • Journal Title

      Dentistry in Japan 42

      Pages: 35-37

    • NAID

      10019595335

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Subcutaneous Injections of a TNF-α Antagonistic Peptide Inhibit Both Inflammation and Bone Resorption in Collagen-Induced Murine Arthritis.2005

    • Author(s)
      Kojima T.
    • Journal Title

      Journal of Dental and Medical Sciences. 52(1)

      Pages: 91-99

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Subcutaneous Injections of a TNF-α Antagonistic Peptide Inhibit Both Inflammation and Bone Resorption in Collagen-Induced Murine Arthritis.2005

    • Author(s)
      Kojima T
    • Journal Title

      Journal of Dental and Medical Sciences 52(1)

      Pages: 91-99

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Subcutaneous Injections of a TNF-α Antagonistic Peptide Inhibit Both Inflammation and Bone Resorption in Collagen-Induced Murine Arthritis.2005

    • Author(s)
      Kojima T, Aoki K, Nonaka K, Saito H, Azuma M, Iwai H, Varghese BJ, Yoshimasu H, Baron R, Ohya K, Amagasa T
    • Journal Title

      Journal of Dental and Medical Sciences 52・1

      Pages: 91-99

    • NAID

      110001065281

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Selective inhibition of NF-kB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo.2004

    • Author(s)
      Jimi E.
    • Journal Title

      Nature Medicine. 10

      Pages: 617-624

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis.2004

    • Author(s)
      Nagahama K.
    • Journal Title

      Bone. 35

      Pages: 1059-1068

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Selective inhibition of NF-kB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo.2004

    • Author(s)
      Jimi E
    • Journal Title

      Nature Medicine 10

      Pages: 617-624

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The deficiency of immunoregulatory receptor PD-1 causes mild osteopetrosis.2004

    • Author(s)
      Nagahama K
    • Journal Title

      Bone 35

      Pages: 1059-1068

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Selective inhibition of NF-kB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo.2004

    • Author(s)
      Jimi F, Aoki K, Saito H, D'Acquisto F, May MJ, Nakamura I, Sudo T, Kojima T, Okamoto F, Fukushima H, Okabe K, Ohya K, Ghosh S
    • Journal Title

      Nature Medicine 10・6

      Pages: 617-624

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A TNF-α antagonist inhibits inflammatory bone resorption induced by Porphyromonas gingivalls infection in mice.

    • Author(s)
      Suzuki Y, Aoki K, Saito H, Umeda M, Nitta H, Baron R, Ohya K.
    • Journal Title

      Journal of Periodontal Research In Press

    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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