Analyzes on ECM metabolism in transgenic and knockout mice

转基因和基因敲除小鼠 ECM 代谢分析

• 批准号: 08044262
• 负责人: OKADA Yasunori
• 金额: $ 7.1万
• 依托单位: School of Medicine, Keio University (1997)Kanazawa University (1996)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044262/
• 关键词: ECM 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

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.

在基质金属蛋白酶（matrix metalloproteinase， MMP）基因家族成员中，MMP-2 （gelatinase A）被认为参与了肿瘤的侵袭转移和关节破坏，因此其在体内的功能很重要。近年来，膜型基质蛋白酶（MT-MMPs）被克隆为proMMP-2的促降解因子，利用MT-MMPs/MMP-2系统降解细胞外基质的机制是MMP研究领域的重点项目之一。在目前的研究中，我们证实了在人浸润性乳腺癌和人甲状腺癌中，MT1-MMP介导了proMMP-2的激活。在人类骨关节炎和类风湿关节炎软骨中，MT1-MMP也在proMMP-2的激活中起主要作用，与软骨破坏呈正相关。我们还发现MT1-MMP是一种细胞外基质降解蛋白酶，能够消化间质胶原和聚集蛋白，同时也是proMMP-2的激活剂。除I型胶原外，MT3-MMP对这些底物具有相似的活性。在软骨中特异性表达MT1-MMP的转基因小鼠已经被制造出来，其表型分析正在进行中。这些小鼠将与日本一组MMP-2基因敲除小鼠进行再杂交，并对其表型进行检测。

项目成果

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)

Nomura H.、Fujimoto N.、Seiki M.、Mai M 和 Okada Y.：“增强人胃癌中基质金属蛋白酶的产生和基质金属蛋白酶 2（明胶酶 A）的激活。”

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)

Yamashita K.、Azumano I.、Mai M. 和 Okada Y.：“基质金属蛋白酶 7（matrylysin）在人胃癌中的表达和组织定位。”

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)

Imai K.：“基质金属蛋白酶对核心蛋白聚糖的降解。切割位点的鉴定、动力学分析和转化生长因子-b1 的释放。”

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)

Imai K.、Hiramatsu A.、Fukushima D.、Pierschbacher M.D. 和 Okada Y.：“基质金属蛋白酶对核心蛋白聚糖的降解。切割位点的鉴定、动力学分析和转化生长因子-b1 释放”Biochem.J.322。

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)

Ohta S.、Imai K.、Yamashita K.、Matsumoto T.、Azumano 和 Okada Y：“基质金属蛋白酶 7（基质溶解素）在人骨关节炎软骨中的表达。”