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Analyzes on ECM metabolism in transgenic and knockout mice

Research Project

Project/Area Number 08044262
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research .
Research Field Experimental pathology
Research InstitutionSchool of Medicine, Keio University (1997)
Kanazawa University (1996)

Principal Investigator

OKADA Yasunori  Keio University, School of Medicine, Pathology, Professor, 医学部, 教授 (00115221)

Co-Investigator(Kenkyū-buntansha) D'ARMIENTO J  コロンビア大学, 医学部・内科学, 助教授
SHIKATA Hideo  School of Dentistry, Meikai University, Pathology, Research Associte, 歯学部・口腔病理, 助手 (00170853)
OHNO Shinsuke  Cancer Research Institute, Kanazawa University, Professor, がん研究所・腫瘍制御, 教授 (70019868)
SHIOZAWA Shuninchi  Kobe University, School of Medicine, Professor, 医学部・保健学科, 教授 (40154166)
CHADA Kiran  UMDNJ-RWJ Medical School, Biochemistry, Associate Professor, 生化学, 助教授
ARMIENTO Jeanine D  Columbia University, School of Medicine, Associate Professor
DARMIENTO Je  コロンビア大学, 医学部・内科学, 助教授
CHADA Kirari  ニュージャージ医科歯科大学, 生化学, 助教授
EECKHOUT Yve  ルーバン大学, 医学部・生化学, 教授
Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥11,100,000 (Direct Cost: ¥11,100,000)
Fiscal Year 1997: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1996: ¥5,400,000 (Direct Cost: ¥5,400,000)
KeywordsECM degradation / Transgenic mice / Matrix metalloproteinase / Tissue destruction / Cancer invasion / Metastasis / ゼラチナーゼA / 膜型MMP / トランスジェニックマウス / ノックアウトマウス
Research Abstract

Among the matrix metalloproteinase (MMP) gene family members, MMP-2 (gelatinase A) is believed to be involved in cancer invasion and metastasis and joint destruction, and thus its function in vivo is important. Membrane-type MMPs (MT-MMPs) were recently cloned as acribators of proMMP-2 and the degradation mechanism of extracellular matrix by the MT-MMPs/MMP-2 system is one of the key projects in the field of MMP research. In the present studies, we have demonstrated that proMMP-2 activation is mediated by MT1-MMP in the human invasive breast carcinomas and human thyroid carcinomas. In the human osteoarthritic and rheumatoid arhtritic cartilages, MT1-MMP also playd a major role in the activation of proMMP-2, showing a positive correlation with cartilage destruction. We also revealed that MT1-MMP is an extracellular matrix-degrading proteinase capable of digesting interstitial collagens and aggrecan as well as an activator of proMMP-2. MT3-MMP had a similar acitivity against these substrates except for type I collagen. Transgenic mice expressing MT1-MMP specifically in the cartilages are being made and analyzes of their phenotypes are now under way. These mice will be back crossed with MMP-2 knockout mice which had been made by a Japanese group and their phenotypes will be examined.

Report

(3 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • Research Products

    (37 results)

All Other

All Publications (37 results)

  • [Publications] Imai K.: "Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and secreted in a complex with tissue inhibitor of metalloproteinases 2." Cancer Res. 56. 2707-2710, (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohuchi E.: "Membrane-type 1-matrix matalloproteinase digests interstitial collagens and other extracellular matrix macromolecules." J.Biol.Chem.272. 2446-2451, (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsunezuka Y.: "Expression of membrane-type matrix metalloproteinase 1(MT1-MMP)in tumor cells enhances pulmonary metastasis in an experimental metastasis assay." Cancer Res.56. 5678-5683, (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K.: "Degradation of decorin by matrix metalloproteinases.Identification of the cleavage sites,kinetic analyses and transforming growth factor-b1 release." Biochem.J.322. 809-814, (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ueno H.: "Expression and tissue localization of membrane-type 1,2 and 3 matrix metalloproteinases in human invasive breast carcinomas." Cancer Res.57. 2055-2060, (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K.: "Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage." Am.J.Pathol.151. 245-256 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nagase H. and Okada Y.: "Proteinases and matrix degradation.Textbook of Rheumatology." W.B.Saunders Company.Philadelphia, 1904 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ueda Y., Imai K., Tsuchiya H., Fujimoto N., Nakanishi I., Katsuda S., Seiki M.and Okada Y.: "Matrix metalloproteinase 9 (gelatinase B) is expressed in multinucleated giant cells of giant cell tumor of bone and is associatd with vascular invasion." Am.J.Pathol.148. 611-622 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Matsuki H., Fujimoto N., Iwata K., Knauper V., Okada Y.and Hayakawa T.: "A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 8 (neutrophil collagenase) using monoclonal antibodies" Clin.Chim.Acta. 244. 129-143 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nomura H., Fujimoto N., Seiki M., Mai M and Okada Y.: "Enhanced production of matrix metalloproteinases and activation of matrix metalloproteinase 2 (gelatinase A) in human gastric carcinomas." Int.J.Cancer. 69. 9-16 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ito.M., Masuda K., It Y., Akizawa T., Yoshioka M., K.Imai, Okada Y., Sato H.and Seiki M.: "Purification and refolding of recombinant human proMMP-7 (pro-matrilysin) expressed in Echelichia coli and its characterization" J.Biochem.119. 667-673 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kinoh H., Sato H., Tunezuka Y., Takino T., Kawashima A., Okada Y.and Seiki M: "MT-MMP,the cell surface activator of pro-MMP-2 (pro-gelatinase A), is expressed with its substrate in the mouse tissue embryogenesis" J Cell Sci. 109. 953-959 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K., Ohuchi E., Aoki T., Nomura H., Fujii Y., Sato H., Seiki M.and Okada Y.: "Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and secreted in a complex with tissue inhibitor of metalloproteinases 2" Cancer Res. 56. 2707-2710 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Sato H., Takino T., Kinoshita T., Imai K., Okaa Y., Stetler-Stevenson W/G.and Seiki M.: "Cell surface binding and activation of gelatinase A induced by expression of membrane-type matrix metalloproteinase-1 (MT-MMP-1)" FEBS Lett. 385. 238-240 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohuchi E., Imai K., Fujii Y., Sato H., Seiki M.and Okada Y.: "Membrane-type 1-matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules." J.Biol.Chem.272. 2446-2451 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Tsunezuka Y., Kinoh H., Takino T., Watanabe Y., Okada Y., Shinagawa A., Sato H.and Seiki M.: "Expression of membrane-type matrix metalloproteinase 1 (MT1-MMP) in tumor cells enhances pulmonary metastasis in an experimental metastasis assay." Cancer Res. 56. 5678-5683 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K., Hiramatsu A., Fukushima D., Pierschbacher M.D.and Okada Y.: "Degradation of decorin by matrix metalloproteinases. Identification of the cleavage sites, kinetic analyzes and transforming growth factor-b1 release" Biochem.J.322. 809-814 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ueno H., Nakamura H., Inoue M., Imai K., Noguchi M., Sato H., Seiki M.and Okada Y.: "Expression and tissue localization of membrane-type 1,2 and 3 matrix metalloproteinases in human invasive breast carcinomas." Cancer Res. 57. 2055-2060 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K., Ohta S., Matsumoto T., Fujimoto N., Sato H., Seiki M.and Okada Y.: "Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage" Am.J.Pathol.151. 245-256 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nagase H.and Okada Y.: "Proteinases and matrix debradation. In Textbook of Rheumatology. Ed.by Kelley W.N., Harris E.D., Jr., Ruddy S.and Sledge C.B.5th edition, W.B.Saunders Company" Philadelphia. 323-341 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohta S., Imai K., Yamashita K., Matsumoto T., Azumano and Okada Y: "Expression of matrix metalloproteinase 7 (matrilysin) in human osteoarthritic cartilage." Lab Invest.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yamashita K., Azumano I., Mai M.and Okada Y.: "Expression and tissue localization of matrix metalloproteinase 7 (matrylysin) in human gastric carcinomas." Int.J.Cancer. (in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nakamura H., Fujii Y., Ohuchi E., Yamamoto E.and Okada Y.: "Human stromelysin 2 : activation of the precursor and interactions with other matrix metalloproteinases. Eur.J.Biochem." Eur.J.Biochem.(in press). (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Imai K.: "Membrane-type matrix metalloproteinase 1 is a gelatinolytic enzyme and secreted in a complex with tissue inhibitor of metalloproteinases 2." Cancer Res.56. 2707-2710 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ohuchi E.: "Membrane-type 1-matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules." J.Biol.Chem.272. 2446-2451 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tsunezuka Y.: "Expression of membrane-type matrix metalloproteinase 1(MT1-MMP)in tumor cells enhances pulmonary metastasis in an experimental metastasis assay." Cancer Res.56. 5678-5683 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Imai K.: "Degradation of decorin by matrix metalloproteinases.Identification of the cleavage sites,kinetic analyses and transforming growth factor-b1 release." Biochem.J.322. 809-814 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ueno H.: "Expression and tissue localization of membrane-type 1,2 and 3 matrix metalloproteinases in human invasive breast carcinomas." Cancer Res.57. 2055-2060 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Imai K.: "Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage." Am.J.Pathol.151. 245-256 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nagase H.and Okada Y.: "Proteinases and matrix degradation.Textbook of Rheumatology." W.B.Saunders Company.Philadelphia, 1904 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kinoh H.,et al.: "MT-MMP,the cell surface activator of proMMP-2(pro-gelatinase A),is expressed with its substrate in the mouse tissue embryogenesis." J.Cell Sci.109. 953-959 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sato H.,et al.: "Cell surface binding and activation of gelatinase A induced by expression of membrane-type matrix metalloproteinase-1(MT-MMP-1)." FEBS Lett.385. 238-240 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ohuchi E.,et al.: "Membrane-type 1-matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules." J.Biol.Chem.272. 2446-2451 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tsunezuka Y.,et al.: "Expression of membrane-type matrix metalloproteinase 1(MT1-MMP)in tumor cells enhances pulmonary metastasis in an experimental metastasis assay." Cancer Res.56. 5678-5683 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ueno H.,et al.: "Expression and tissue localization of membranetype 1,2 and 3 matrix metalloproteinases in human invasive breast carcinomas." Cancer Res.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Imai K.,et al.: "Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage." Am.J.Pathol.(in press). (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nagase H.and Okada Y.: "Textbook of Rheumatology." W.B.Saunders Company,Philadelphia, 1904 (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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