Generation of an animal model and identification of therapeutic targets for auto-inflammatory syndrome

• Project/Area Number: 16K10917
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: Miyamoto Kana 慶應義塾大学, 医学部(信濃町), 研究員 (60464997)
• Research Collaborator: OIKE Takatsugu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 関節疾患 / 自己炎症性疾患 / 炎症性疾患 / 自己炎症症候群 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Auto-inflammatory syndrome is a disease characterized by systemic inflammation in tissues such as major joints, and is distinct from rheumatoid arthritis (RA), which exhibits minor joint inflammation. However, since auto-inflammatory syndrome is a rare disease, and the appropriate animal models were not generated, underlying pathological mechanisms have not been clarified nor are treatment strategies established. In this study, we successfully established a new mouse model in which IL-1 signaling was conditionally activated in adult mice (cTg), and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. We found that levels of serum IL-6 and IL-17 were elevated and Stat3 was activated in joints of cTg mice. Phenotypes seen in cTg mice were ameliorated by crossing cTg mice with either IL-6 KO, IL-17 KO or Stat3 cKO mice. Thus, we concluded that IL-6, IL-17 and Stat3 all represent potential therapeutic targets for Auto-inflammatory syndrome.

Academic Significance and Societal Importance of the Research Achievements

自己炎症症候群は大関節優位の関節炎を発症するなど、小関節優位の関節炎を発症する関節リウマチ（RA）とは区別される。しかし、自己炎症症候群は患者数が少ないことや動物モデルが樹立されていないこともあり、その病態解明や治療法の開発は進んでいなかった。本研究では、自己炎症症候群の表現型を再現する動物モデルを新規に樹立し、その解析からIL-6、IL-17およびStat3が自己炎症症候群の治療標的となり得ることを示し得た点で、学術的また社会的意義があると考えている。

Research Products

• [Journal Article] Insulin-like growth factor-I is required to maintain muscle volume in adult mice. (2019)
  • Author(s): Nakamura S, Sato Y, Kobayashi T, Oike T, Kaneko Y, Miyamoto K, Funayama A, Oya A, Nishiwaki T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab. Volume: 印刷中 Issue: 4 Pages: 627-635
  • DOI: 10.1007/s00774-018-0964-6
  • Peer Reviewed
• [Journal Article] Elevated Creatine Kinase and Lactic Acid Dehydrogenase and Decreased Osteocalcin and Uncarboxylated Osteocalcin are Associated with Bone Stress Injuries in Young Female Athletes (2018)
  • Author(s): Miyamoto T, Oguma Y, Sato Y, Kobayashi T, Ito E, Tani M, Miyamoto K, Nishiwaki Y, Ishida H, Otani T, Matsumoto H, Matsumoto M, Nakamura M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 18019-18019
  • DOI: 10.1038/s41598-018-36982-0
  • Peer Reviewed / Open Access
• [Journal Article] IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse. (2018)
  • Author(s): Oike T, Kanagawa H, Sato Y, Kobayashi T, Nakatsukasa H, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Yoshimura A, Iwakura Y, Takeuchi T, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: - Issue: 1 Pages: 15783-15783
  • DOI: 10.1038/s41598-018-34173-5
  • Peer Reviewed / Open Access
• [Journal Article] Tumor necrosis factor receptor-associated factor 6 is required to inhibit foreign body giant cell formation and activate osteoclasts under inflammatory and infectious conditions (2018)
  • Author(s): Oya A, Katsuyama E, Morita M, Sato Y, Kobayashi T, Miyamoto K, Nishiwaki T, Funayama A, Fujita Y, Kobayashi T, Matsumoto M, Nakamura M, Kanaji A, Miyamoto T.
  • Journal Title: J Bone Miner Metab Volume: - Issue: 6 Pages: 679-690
  • DOI: 10.1007/s00774-017-0890-z
  • Peer Reviewed
• [Journal Article] Metabolomics-based profiles predictive of low bone mass in menopausal women. (2018)
  • Author(s): Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Soga T, Tomita M, Nakamura M, Matsumoto M.
  • Journal Title: Bone Rep Volume: 9 Pages: 11-18
  • DOI: 10.1016/j.bonr.2018.06.004
  • Peer Reviewed / Open Access
• [Journal Article] Stat3 as a potential therapeutic target for rheumatoid arthritis. (2017)
  • Author(s): Oike T, Sato Y, Kobayashi T, Miyamoto K, Nakamura S, Kaneko Y, Kobayashi S, Harato K, Saya H, Matsumoto M, Nakamura M, Niki Y, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 10965-10965
  • DOI: 10.1038/s41598-017-11233-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enpp1 is an anti-aging factor that regulates Klotho under phosphate overload conditions. (2017)
  • Author(s): Watanabe R, Fujita N, Sato Y, Kobayashi T, Morita M, Oike T, Miyamoto K, Kuro-O M, Michigami T, Fukumoto S, Tsuji T, Toyama Y, Nakamura M, Matsumoto M, Miyamoto T.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 7786-7786
  • DOI: 10.1038/s41598-017-07341-2
  • NAID: 120006535028
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of pro-inflammatory cytokine levels following anti-resorptive drug treatment is required for osteonecrosis development in infectious osteomyelitis (2017)
  • Author(s): Morita M, Iwasaki R, Sato Y, Kobayashi T, Watanabe R, Oike T, Nakamura S, Keneko Y, Miyamoto K, Ishihara K, Iwakura Y, Ishii K, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 46322-46322
  • DOI: 10.1038/srep46322
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The nicotinic acetylcholine receptor α7 subunit is an essential negative regulator of bone mass. (2017)
  • Author(s): Mito K, Sato Y, Kobayashi T, Miyamoto K, Nitta E, Iwama A, Matsumoto M, Nakamura M, Sato K, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 45597-45597
  • DOI: 10.1038/srep45597
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A missense single nucleotide polymorphism in the ALDH2 gene, rs671, is associated with hip fracture. (2017)
  • Author(s): Takeshima K, Nishiwaki Y, Suda Y, Niki Y, Sato Y, Kobayashi T, Miyamoto K, Uchida H, Inokuchi W, Tsuji T, Funayama A, Nakamura M, Matsumoto M, Toyama Y, Miyamoto T.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 428-428
  • DOI: 10.1038/s41598-017-00503-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A serum metabolomics-based profile in low bone mineral density postmenopausal women. (2017)
  • Author(s): Miyamoto T, Hirayama A, Sato Y, Koboyashi T, Katsuyama E, Kanagawa H, Miyamoto H, Mori T, Yoshida S, Fujie A, Morita M, Watanabe R, Tando T, Miyamoto K, Tsuji T, Funayama A, Nakamura M, Matsumoto M, Soga T, Tomita M, Toyama Y.
  • Journal Title: Bone Volume: 95 Pages: 1-4
  • DOI: 10.1016/j.bone.2016.10.027
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis (2017)
  • Author(s): Sato Y, Tando T, Morita M, Miyamoto K, Kobayashi T, Watanabe R, Oike T, Matsumoto M, Nakamura M, Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun Volume: 482 Issue: 4 Pages: 1430-1436
  • DOI: 10.1016/j.bbrc.2016.12.053
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ibandronate concomitantly blocks immobilization-induced bone and muscle atrophy. (2016)
  • Author(s): Watanabe R, Fujita N, Takeda S, Sato Y, Kobayashi T, Morita M, Oike T, Miyamoto K, Matsumoto Y, Matsumoto M, Nakamura M, Miyamoto T.
  • Journal Title: Biochem Biophys Res Commun Volume: 480 Issue: 4 Pages: 662-668
  • DOI: 10.1016/j.bbrc.2016.10.112
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective Estrogen Receptor Modulators Suppress Hif1α Protein Accumulation in Mouse Osteoclasts (2016)
  • Author(s): Morita M, Sato Y, Iwasaki R, Kobayashi T, Watanabe R, Oike T, Miyamoto K, Toyama Y, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: PLoS One Volume: 11 Issue: 11 Pages: e0165922-e0165922
  • DOI: 10.1371/journal.pone.0165922
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smad4 is required to inhibit osteoclastogenesis and maintain bone mass (2016)
  • Author(s): Morita M, Yoshida S, Iwasaki R, Yasui T, Sato Y, Kobayashi T, Watanabe R, Oike T, Miyamoto K, Takami M, Ozato K, Deng CX, Aburatani H, Tanaka S, Yoshimura A, Toyama Y, Matsumoto M, Nakamura M, Kawana H, Nakagawa T, Miyamoto T.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 35221-35221
  • DOI: 10.1038/srep35221
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy (2016)
  • Author(s): Tando T, Hirayama A, Furukawa M, Sato Y, Kobayashi T, Funayama A, Kanaji A, Hao W, Watanabe R, Morita M, Oike T, Miyamoto K, Soga T, Nomura M, Yoshimura A, Tomita M, Matsumoto M, Nakamura M, Toyama Y, Miyamoto T
  • Journal Title: J Biol Chem Volume: 291 Issue: 23 Pages: 12184-94
  • DOI: 10.1074/jbc.m115.680579
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vitamin D Deficiency with High Intact PTH Levels is More Common in Younger than in Older Women: A Study of Women Aged 39–64 Years (2016)
  • Author(s): Miyamoto T, Katsuyama E, Kanagawa H, Fujie A, Miyamoto H, Yoshida S, Mori T, Miyamoto K, Sato Y, Kobayashi T, Nakamura M, Matsumoto M, Nishiwaki Y, Hirose H, Kanda T, Saito I, Toyama Y.
  • Journal Title: The Keio Journal of Medicine Volume: 65 Issue: 2 Pages: 33-38
  • DOI: 10.2302/kjm.2015-0010-OA
  • NAID: 130005158314
  • ISSN: 0022-9717, 1880-1293
  • Peer Reviewed / Acknowledgement Compliant