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

• Project/Area Number: 16K15661
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Nagoya 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: ¥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)
• Keywords: Dkk1 / 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.

Research Products

• [Journal Article] Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling (2017)
  • 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 Issue: 9 Pages: e0184388-e0184388
  • DOI: 10.1371/journal.pone.0184388
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [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 study (2017)
  • 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: Mod Rheumatol. Volume: 28(2) Issue: 2 Pages: 221-226
  • DOI: 10.1080/14397595.2017.1332558
  • NAID: 120006648042
  • 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 adalimumab (2017)
  • 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: Mod Rheumatol Volume: 28 Issue: 1 Pages: 119-125
  • DOI: 10.1080/14397595.2017.1317320
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-inducible factor-2α induces expression of type X collagen and matrix metalloproteinases 13 in osteoarthritic meniscal cells (2016)
  • 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） Issue: 6 Pages: 439-48
  • DOI: 10.1007/s00011-016-0926-1
  • 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） Issue: 3 Pages: 469-475
  • DOI: 10.1016/j.bbrc.2016.09.085
  • 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
  • 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） Issue: 6 Pages: 1246-1250
  • DOI: 10.1016/j.arth.2015.12.014
  • Peer Reviewed
• [Presentation] Analysis of Tendon-related Genes and Angiogenesis-related Genes in Tendon-like Cells (2017)
  • 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
  • Int'l Joint Research
• [Presentation] Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling (2017)
  • 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
  • Int'l Joint Research
• [Presentation] Promethazine hydrochloride inhibits ectopic fat formation in skeletal muscle (2017)
  • 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
  • Int'l Joint Research
• [Presentation] Short-range ultraviolet irradiation with LED device effectively increases serum levels of 25(OH)D (2017)
  • 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
  • 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.
• [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