Inhibition of chronic arthritis and joint destruction by targeting Stat3

• Project/Area Number: 19K09655
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kumamoto University (2020-2021); Keio University (2019)
• Principal Investigator: Miyamoto Kana 熊本大学, 病院, 医員 (60464997)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / 関節炎 / 整形外科

Outline of Research at the Start

関節リウマチに代表される関節炎疾患は、関節痛や関節腫脹だけではなく、関節の変形や日常生活動作レベルの低下に直結することから、その対策は重要です。本研究では、関節リウマチモデルマウスや新規に樹立した自己炎症症候群モデルマウスを用いて、関節炎および関節破壊を抑制する、新たな治療薬開発を進めます。

Outline of Final Research Achievements

We screened approximately 4.9 million small compounds as potential inhibitors of Stat3 using in silico screening, and identified 39 candidates as potential Stat3 inhibitors. We then tested available 15 compounds out of 39 their Stat3 inhibiting activity in in vitro secondary screen. We found that 3 out 15 had potential Stat3 inhibiting activities in vitro, thus we analyzed the effects of these 3 compounds in collagen induced arthritis (CIA) model, a rheumatoid arthritis model, in vivo. One out of 3 compounds significantly inhibited arthritis development without apparent adverse effects in CIA models in vivo. Finally, we confirmed that the one compound significantly blocked Stat3 phosphorylation induced by IL-6 in vitro.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ（RA）は慢性的に経過する関節炎や関節破壊のため、ADLやQOLが著しく障害される慢性炎症性疾患である。今日、炎症性サイトカインやシグナル分子であるJakを標的とした分子標的治療が発展しているが、転写因子を標的とした治療法は開発されていない。今回、転写因子であるStat3の阻害によりRAに対する治療効果の可能性を示した点並びにStat3阻害効果をin vivoおよびin vitroで発揮する低分子化合物を同定した点で学術的意義がある。また、既存の治療法では寛解を得られない患者も少なくなく、価格的に安価な低分子化合物で新たな治療法の選択肢を提案した点で社会的意義もあると考えている。

Research Products

• [Journal Article] Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics (2022)
  • Author(s): Soma Tomoya、Iwasaki Ryotaro、Sato Yuiko、Kobayashi Tami、Ito Eri、Matsumoto Tatsuaki、Kimura Atsushi、Miyamoto Kana、Matsumoto Morio、Nakamura Masaya、Morita Mayu、Asoda Seiji、Kawana Hiromasa、Nakagawa Taneaki、Miyamoto Takeshi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-021-03966-6
  • Peer Reviewed / Open Access
• [Journal Article] Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo (2022)
  • Author(s): Kimura Atsushi、Hirayama Akiyoshi、Matsumoto Tatsuaki、Sato Yuiko、Kobayashi Tami、Ikeda Satsuki、Maruyama Midori、Kaneko Mari、Shigeta Mayo、Ito Eri、Soma Tomoya、Miyamoto Kana、Soga Tomoyoshi、Tomita Masaru、Oya Akihito、Matsumoto Morio、Nakamura Masaya、Kanaji Arihiko、Miyamoto Takeshi
  • Journal Title: Metabolites Volume: 12 Issue: 1 Pages: 82-82
  • DOI: 10.3390/metabo12010082
  • Peer Reviewed / Open Access
• [Journal Article] Transient alendronate administration to pregnant or lactating mothers prevents bone loss in mice without adverse effects on offspring (2021)
  • Author(s): Ito Eri、Sato Yuiko、Kobayashi Tami、Soma Tomoya、Matsumoto Tatsuaki、Kimura Atsushi、Miyamoto Kana、Matsumoto Hideo、Matsumoto Morio、Nakamura Masaya、Sato Kazuki、Miyamoto Takeshi
  • Journal Title: Bone Volume: 153 Pages: 116133-116133
  • DOI: 10.1016/j.bone.2021.116133
  • Peer Reviewed
• [Journal Article] A Metabolomic Profile Predictive of New Osteoporosis or Sarcopenia Development (2021)
  • Author(s): Miyamoto Kana、Hirayama Akiyoshi、Sato Yuiko、Ikeda Satsuki、Maruyama Midori、Soga Tomoyoshi、Tomita Masaru、Nakamura Masaya、Matsumoto Morio、Yoshimura Noriko、Miyamoto Takeshi
  • Journal Title: Metabolites Volume: 11 Issue: 5 Pages: 278-278
  • DOI: 10.3390/metabo11050278
  • Peer Reviewed / Open Access
• [Journal Article] Synoviolin is not a pathogenic factor for auto-inflammatory diseases (2021)
  • Author(s): Matsumoto Tatsuaki、Sato Yuiko、Kobayashi Tami、Ito Eri、Soma Tomoya、Kimura Atsushi、Miyamoto Kana、Kobayashi Shu、Harato Kengo、Matsumoto Morio、Nakamura Masaya、Niki Yasuo、Miyamoto Takeshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 558 Pages: 183-188
  • DOI: 10.1016/j.bbrc.2021.04.093
  • Peer Reviewed
• [Journal Article] Treatment with an active vitamin D analogue blocks hypothalamic dysfunction-induced bone loss in mice (2021)
  • Author(s): Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 542 Pages: 48-53
  • DOI: 10.1016/j.bbrc.2021.01.026
  • Peer Reviewed
• [Journal Article] Food restriction reduces cortical bone mass and serum insulin-like growth factor-1 levels and promotes uterine atrophy in mice (2021)
  • Author(s): Ito E, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Soma T, Matsumoto T, Kimura A, Miyamoto K, Matsumoto H, Matsumoto M, Nakamura M, Sato K, Miyamoto T
  • Journal Title: Biochem Biophys Res Commun Volume: 534 Pages: 165-171
  • DOI: 10.1016/j.bbrc.2020.11.122
  • Peer Reviewed
• [Journal Article] ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress (2021)
  • Author(s): Kobayashi H, Nakamura S, Sato Y, Kobayashi T, Miyamoto K, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T
  • Journal Title: Bone Volume: 142 Pages: 115739-115739
  • DOI: 10.1016/j.bone.2020.115739
  • Peer Reviewed
• [Journal Article] Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw (2020)
  • Author(s): Soma T, Iwasaki R, Sato Y, Kobayashi T, Nakamura S, Kaneko Y, Ito E, Okada H, Watanabe H, Miyamoto K, Matsumoto M, Nakamura M, Asoda S, Kawana H, Nakagawa T, Miyamoto T
  • Journal Title: J Bone Miner Metab Volume: - Issue: 3 Pages: 372-384
  • DOI: 10.1007/s00774-020-01174-2
  • Peer Reviewed
• [Journal Article] Smoking cessation increases levels of osteocalcin and uncarboxylated osteocalcin in human sera (2020)
  • Author(s): Kiyota Y, Muramatsu H, Sato Y, Kobayashi T, Miyamoto K, Iwamoto T, Matsumoto M, Nakamura M, Tateno H, Sato K, Miyamoto T
  • Journal Title: Sci Rep Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-73789-4
  • Peer Reviewed / Open Access
• [Journal Article] Vitamin D protects against immobilization-induced muscle atrophy via neural crest-derived cells in mice (2020)
  • Author(s): Nakamura S, Sato Y, Kobayashi T, Kaneko Y, Ito E, Soma T, Okada H, Miyamoto K, Oya A, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T
  • Journal Title: Sci Rep Volume: 10 Issue: 1
  • DOI: 10.1038/s41598-020-69021-y
  • Peer Reviewed / Open Access
• [Journal Article] Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model. (2019)
  • Author(s): Kaneko Y, Tanigawa N, Sato Y, Kobayashi T, Nakamura S, Ito E, Soma T, Miyamoto K, Kobayashi S, Harato K, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 18741-18741
  • DOI: 10.1038/s41598-019-55297-2
  • Peer Reviewed / Open Access
• [Journal Article] Changes in bone metabolic profile associated with pregnancy or lactation. (2019)
  • Author(s): Miyamoto T, Miyakoshi K, Sato Y, Kasuga Y, Ikenoue S, Miyamoto K, Nishiwaki Y, Tanaka M, Nakamura M, Matsumoto M.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 6787-6787
  • DOI: 10.1038/s41598-019-43049-1
  • Peer Reviewed / Open Access