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Development of a new drug for treating osteoarthritis caused by increased expression of Dkk1 molecule

Research Project

Project/Area Number 16K15661
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Orthopaedic surgery
Research InstitutionNagoya University

Principal Investigator

Ishiguro Naoki  名古屋大学, 医学系研究科, 教授 (20212871)

Co-Investigator(Kenkyū-buntansha) 酒井 忠博  名古屋大学, 医学系研究科, 准教授 (60378198)
平岩 秀樹  名古屋大学, 医学部附属病院, 病院講師 (70566976)
高橋 伸典  名古屋大学, 医学部附属病院, 病院講師 (20570196)
Project Period (FY) 2016-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsDkk1 / Wnt signal / β - catenin / Drug repositioning / Wnt/βcatenin / DKK1 / Wntシグナル / 変形性関節症
Outline of Final Research Achievements

We could not find a compound with an enhancing effect on Dkk1 expression. As a cause, we considered the possibility that β - catenin mutation induces the increasing of Wnt signal. Dkk1 is a target gene of Wnt signal, and Dkk1 production is enhanced in cells that are enhanced. Considering the possibility that the enhancing action of the drug is difficult to detect in such Dkk1 producing cells, two kinds of compounds were obtained by changing the cells. These drugs were able to confirm Dkk1 expression enhancing action even at the level of mRNA. However, in the luciferase assay by TOP flash, the Wnt signal activity increased and the opposite result was obtained. The goal of the research was changed to a new development of a drug having a Dkk1 expression lowering action. At present, one kind of drug is selected to confirm the reduction of Dkk1 expression at the mRNA level and the activity of decreasing the activity of Wnt signal. We are continuing the examination.

Report

(3 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report

Research Products

(17 results)

All 2018 2017 2016

All Journal Article (11 results) (of which Peer Reviewed: 11 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Predictors of biologic discontinuation due to insufficient response in patients with rheumatoid arthritis who achieved clinical remission with biologic treatment: A multicenter observational cohort study2018

    • Author(s)
      Asai S, Fujibayashi T, Oguchi T, Hanabayashi M, Hayashi M, Matsubara H, Ito T, Yabe Y, Watanabe T, Hirano Y, Kanayama Y, Kaneko A, Kato T, Takagi H, Takahashi N, Funahashi K, Takemoto T, Asai N, Watanabe T, Ishiguro N, Kojima T
    • Journal Title

      Modern Rheumatology

      Volume: 28(2) Pages: 221-226

    • DOI

      10.1080/14397595.2017.1332558

    • NAID

      120006648042

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High rate of improvement in serum matrix metalloproteinase-3 levels at 4 weeks predicts remission at 52 weeks in RA patients treated with adalimumab2018

    • Author(s)
      Hattori Yosuke、Kojima Toshihisa、Kaneko Atsushi、Kida Daihei、Hirano Yuji、Fujibayashi Takayoshi、Yabe Yuichiro、Oguchi Takeshi、Kanayama Yasuhide、Miyake Hiroyuki、Kato Takefumi、Takagi Hideki、Hayashi Masatoshi、Ito Takayasu、Shioura Tomone、Takahashi Nobunori、Ishikawa Hisato、Funahashi Koji、Ishiguro Naoki
    • Journal Title

      Modern Rheumatology

      Volume: 28 Pages: 119-125

    • DOI

      10.1080/14397595.2017.1317320

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling2017

    • Author(s)
      Miyamoto Kentaro、Ohkawara Bisei、Ito Mikako、Masuda Akio、Hirakawa Akihiro、Sakai Tadahiro、Hiraiwa Hideki、Hamada Takashi、Ishiguro Naoki、Ohno Kinji
    • Journal Title

      PLOS ONE

      Volume: 12

    • DOI

      10.1371/journal.pone.0184388

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 小児膝伸展機構損傷後に膝蓋腱骨化を生じた2例2017

    • Author(s)
      宮本健太郎,小田智之,黒河内和俊,高橋成夫,平岩秀樹,濱田恭,山下暁士,岸本烈純,土谷早穂,酒井忠博
    • Journal Title

      JOSKAS

      Volume: 42(2) Pages: 364-365

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] スポーツで受傷した膝複合靱帯損傷に総腓骨神経損傷を合併した2例2017

    • Author(s)
      酒井忠博,平岩秀樹,濱田恭,小田智之,山下暁士,宮本健太郎,岸本烈純,土谷早穂,大羽宏樹,川村佑介
    • Journal Title

      JOSKAS

      Volume: 42(2) Pages: 370-371

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coxitis kneeに対する人工膝関節置換術の治療成績2017

    • Author(s)
      濱田 恭, 平岩 秀樹, 小田 智之, 山下 暁士, 宮本 健太郎, 岸本 烈純, 土谷 早穂, 川村 佑介, 大羽 宏樹, 酒井 忠博
    • Journal Title

      JOSKAS

      Volume: 42(2) Pages: 296-297

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 反復性肩関節脱臼に対する空気を用いた関節造影CTの診断能の検討2017

    • Author(s)
      平岩 秀樹, 酒井 忠博, 濱田 恭, 大野 洋平, 小田 智之, 山下 暁士, 宮本 健太郎, 岸本 烈純, 土谷 早穂, 大羽 宏樹, 川村 佑介
    • Journal Title

      肩関節

      Volume: 41(3) Pages: 649-652

    • NAID

      130006195195

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hypoxia-inducible factor-2α induces expression of type X collagen and matrix metalloproteinases 13 in osteoarthritic meniscal cells2016

    • Author(s)
      Ishizuka S,Sakai T,Hiraiwa H,Hamada T,Warren K,Ono Y,Nakashima M,Matsukawa T,Oda T,Takamatsu A,Yamashita S,Ishiguro N
    • Journal Title

      Inflammation Research

      Volume: 65(6) Pages: 439-48

    • DOI

      10.1007/s00011-016-0926-1

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Osteoarthritis-derived chondrocytes are a potential source of multipotent progenitor cells for cartilage tissue engineering.2016

    • Author(s)
      Oda T, Sakai T, Hiraiwa H, Hamada T, Ono Y, Nakashima M, Ishizuka S, Matsukawa T, Yamashita S, Tsuchiya S, Ishiguro N.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 479(3) Pages: 469-475

    • DOI

      10.1016/j.bbrc.2016.09.085

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Validity of a tablet computer version of the Japanese Orthopaedic Association hip disease evaluation questionnaire: a pilot study.2016

    • Author(s)
      Takegami Y, Seki T, Kaneuji A, Nakao A, Hasegawa Y, Ishiguro N.
    • Journal Title

      Nagoya Journal of Medical Science

      Volume: 78(3) Pages: 237-244

    • NAID

      120005837925

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Significantly Lower Wear of Ceramic-on-Ceramic Bearings Than Metal-on-Highly Cross-Linked Polyethylene Bearings: A 10- to 14-Year Follow-Up Study.2016

    • Author(s)
      Higuchi Y, Hasegawa Y, Seki T, Komatsu D, Ishiguro N.
    • Journal Title

      The Journal of arthroplasty

      Volume: 31(6) Pages: 1246-1250

    • DOI

      10.1016/j.arth.2015.12.014

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] Analysis of Tendon-related Genes and Angiogenesis-related Genes in Tendon-like Cells2017

    • Author(s)
      Saho Tsuchiya, Tadahiro Sakai, Hideki Hiraiwa, Takashi Hamada, Yohei Ono, Tomoyuki Oda, Satoshi Yamashita Kentaro Miyamoto, Yasuzumi Kishimoto, Yusuke Kawamura, Hiroki Oba, Naoki Ishiguro
    • Organizer
      2017 Annual Meeting of Orthopaedic Research Society
    • Place of Presentation
      サンディエゴ(アメリカ)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling2017

    • Author(s)
      Kentaro Miyamoto,Bisei Ohkawara,Akihiro Hirakawa,Tadahiro Sakai,Hideki Hiraiwa,Takashi Hamada,Kinji Ohno,Naoki Ishiguro
    • Organizer
      2017 Annual Meeting of Orthopaedic Research Society
    • Place of Presentation
      サンディエゴ(アメリカ)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Promethazine hydrochloride inhibits ectopic fat formation in skeletal muscle2017

    • Author(s)
      Takehiro Kasai, Akiyoshi Uezumi, Masashi Nakatani, Naoki Ishiguro, Kinji Ohno, Harumoto Yamada, Kunihiro Tsuchida
    • Organizer
      2017 Annual Meeting of Orthopaedic Research Society
    • Place of Presentation
      サンディエゴ(アメリカ)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Short-range ultraviolet irradiation with LED device effectively increases serum levels of 25(OH)D2017

    • Author(s)
      Daigo Morita, Yoshihiro Nishida, Yoshitoshi Higuchi, Taisuke Seki, Kunihiro Ikuta, Naoki Ishiguro
    • Organizer
      2017 Annual Meeting of Orthopaedic Research Society
    • Place of Presentation
      サンディエゴ(アメリカ)
    • Year and Date
      2017-03-19
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of drugs for osteoarthritis by the increasing expression of DKK-1 : Making construct of DKK-1 promoter incorporated in pGL4.10.2017

    • Author(s)
      西梅 剛, 高橋伸典, 小嶋俊久, 石黒 直樹, 大河原美静, 大野欣司
    • Organizer
      第30回日本軟骨代謝学会.
    • Related Report
      2017 Annual Research Report
  • [Presentation] Wnt/β・カテニンシグナル経路は腱関連遺伝子発見に影響を与える2017

    • Author(s)
      岸本烈純,大河原美静,酒井忠博,平岩秀樹,濱田恭,大野洋平,山下暁士,小田智之,土谷早穂,大野欽司,石黒直樹
    • Organizer
      第90回日本整形外科学会学術総会
    • Related Report
      2017 Annual Research Report

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Published: 2016-04-21   Modified: 2019-03-29  

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