Clinical significance of MMPs and TIMPs in pathogenesis of patients with recurrent pregnancy loss

• Project/Area Number: 16K11100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Nagoya City University
• Principal Investigator: Ozaki Yasuhiko 名古屋市立大学, 大学院医学研究科, 教授 (50254280)
• Research Collaborator: Goto Shinobu ; Sugiura Mayumi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 不育症 / 習慣流産 / プロテアーゼ / MMP / TIMP / 脱落膜 / 頸管粘液 / 反復流産 / 絨毛 / d-ROM / BAP / 子宮頸管粘液 / 子宮内膜機能 / 非侵襲的臨床検査法 / バイオマーカー

Outline of Final Research Achievements

We investigated the role of MMPs and TIMPs in recurrent pregnancy loss (RPL). The expression of MMP-2 in decidua with normal chromosome group (NC) was significantly lower than in abnormal chromosome group (AC) . And the expression of MMP-9 in decidua with NC is significantly higher than in AC. The staining of MMP-2 and TIMP-2 were observed in stromal cells and in cytoplasm of only AC. MMP-9 and TIMP-1 were observed in stromal cells. Concentration of MMP-2 in plasma with APS(-) (n=10) was significantly lower than in control and MMP-9 in patients was significantly higher than control. Concentration of TIMP-1 in plasma with APS(-) was significantly lower than APS(+) . The ratio of MMP9/TIMP1 in plasma with patient was significantly higher than control and ratio of MMP2/TIMP2 in APS(-) group was significantly lower than APS(+) . These results suggested that MMPs and TIMPs play an important role in pathogenesis of RPL and that they can be one of the predictive factors in patients with RPL.

Academic Significance and Societal Importance of the Research Achievements

不育症の約25％が原因不明であり、我々はそれらにおけるプロテアーゼの関与を検討してきた。今回の検討より、妊娠初期の脱落膜組織におけるMMP-2の発現の低下が間質における絨毛の浸潤不全を介して流産を惹起している可能性が考えられた。また好中球の活性化によるMMP-9の増加が好中球エラスターゼやカテプシンGの活性化を制御して感染性の流産病態を惹起している可能性があると思われた。また非侵襲的な不育症（流産）の予知マーカーとして、子宮頸管粘液中のMMPやTIMPの応用できる可能性を示すことができた。

Research Products

• [Journal Article] １、切迫早産の新しい概念と管理法、子宮頸管ペッサリーによる切迫早産治療法 (2018)
  • Author(s): 尾崎康彦
  • Journal Title: 日本産科婦人科学会雑誌 Volume: 70 Pages: 2213-2217
• [Journal Article] Failure to improve after ovarian resection could be a marker of recurrent ovarian teratoma in anti-NMDAR encephalitis: a case report. (2018)
  • Author(s): Uchida Y, Kato D, Yamashita Y, Ozaki Y, Matsukawa N
  • Journal Title: Neuropsychiatr Dis Treat. Volume: 14 Pages: 339-342
  • DOI: 10.2147/ndt.s156603
  • Peer Reviewed / Open Access
• [Journal Article] Genotyping analysis of the factor V Nara mutation, Hong Kong mutation, and 16 single-nucleotide polymorphisms, including the R2 haplotype, and the involvement of factor V activity in patients with recurrent miscarriage. (2017)
  • Author(s): Izuhara M, Shinozawa K, Kitaori T, Katano K, Ozaki Y, Fukutake K, Sugiura-Ogasawara M
  • Journal Title: Blood Coagul Fibrinolysis Volume: 28 Issue: 4 Pages: 323-328
  • DOI: 10.1097/mbc.0000000000000598
  • Peer Reviewed / Open Access
• [Journal Article] Genotyping analysis of protein S-Tokushima (K196E) and the involvement of protein S antigen and activity in patients with recurrent pregnancy loss (2017)
  • Author(s): Matsukawa Y, Asano E, Tsuda T, Kuma H, Kitaori T, Katano K, Ozaki Y, Sugiura- Ogasawara M
  • Journal Title: Eur J Obstet Gynecol Reprod Biol Volume: 211 Pages: 90-97
  • DOI: 10.1016/j.ejogrb.2017.01.056
  • Peer Reviewed / Open Access
• [Journal Article] The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome (2017)
  • Author(s): Sugiura-Ogasawara Mayumi、Omae Yosuke、Kawashima Minae、Toyo-Oka Licht、Khor Seik-Soon、Sawai Hiromi、Horita Tetsuya、Atsumi Tatsuya、Murashima Atsuko、Fujita Daisuke、Fujita Tomio、Morimoto Shinji、Morishita Eriko、Katsuragi Shinji、Kitaori Tamao、Katano Kinue、Ozaki Yasuhiko、Tokunaga Katsushi
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 9 Pages: 831-838
  • DOI: 10.1038/jhg.2017.46
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in patients with recurrent miscarriag (2016)
  • Author(s): Yuki Obayashi, Yasuhiko Ozaki, Satomi Kurakane, Shinobu Goto, Kyoko Kumagai, Tamao Kitaori, Suzumori Nobuhiro, Mayumi Sugiura
  • Journal Title: American Journal of Reproductive Immunology Volume: 75 Issue: 1 Pages: 69-77
  • DOI: 10.1111/aji.12434
  • Peer Reviewed
• [Presentation] 不育症病態における酸化ストレス度と抗酸化力の役割と意義 (2018)
  • Author(s): 尾崎康彦、後藤志信、井出祥子、小澤史子、北折珠央、杉浦真弓
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] 切迫早産の新しい概念と管理法、子宮頸管ペッサリーにより切迫早産治療法 (2018)
  • Author(s): 尾崎康彦
  • Organizer: 第70回日本産科婦人科学会学術講演会
• [Presentation] 反復流産病態におけるMMP-2およびMMP-9遺伝子の一塩基多型 (2017)
  • Author(s): 森亮介、尾崎康彦、大林勇輝、後藤志信、松川泰、北折珠央、杉浦真弓
  • Organizer: 第69回日本産科婦人科学会学術集会
• [Presentation] 反復流産病態におけるMMPsおよびTIMPsの存在と意義 (2017)
  • Author(s): 小澤史子、森亮介、大林勇輝、後藤志信、北折珠央、古野忠秀、杉浦真弓、尾崎康彦
  • Organizer: 第22回日本病態プロテアーゼ学会
• [Presentation] ROLE OF MATRIX METALLOPROTEINASE-2 and 9 IN PATHOGENESIS OF PATIENTS WITH RECURRENT PREGNANCY LOSS (2016)
  • Author(s): Yasuhiko Ozaki, Shinobu Goto, Fumiko Ozawa, Yuki Obayashi, Yasushi Matsukawa, Ryosuke Mori, Mayumi Sugiura-Ogasawara
  • Organizer: XIV Symposium on Proteinase Inhibitors and Biologocal Control
  • Place of Presentation: Portorose, Slovenia
  • Year and Date: 2016-09-05
  • Int'l Joint Research / Invited
• [Book] 実践臨床生殖免疫学 (2018)
  • Author(s): 尾崎康彦、杉浦真弓
  • Publisher: 中外医学社
• [Book] ヒト精子の受精能獲得におけるカルパインの役割（Role of Calpain in Human Sperm） (2018)
  • Author(s): 尾崎康彦、清田朋美、梅本幸裕、杉浦真弓
  • Publisher: Reproductive Immunology and Biology
• [Book] 不妊・不育診療指針 (2016)
  • Author(s): 尾崎康彦、杉浦真弓、柴原浩章 他
  • Total Pages: 556
  • Publisher: 中外医学社
• [Remarks] 名古屋市立大学不育症研究センター
  • URL: http://www.med.nagoya-cu.ac.jp/w3med/news/rc_recurrent_pregnancy_loss.html