Pathological studies on the tissue destruction by metalloproteinases

金属蛋白酶组织破坏的病理学研究

• 批准号: 16209015
• 负责人: OKADA Yasunori
• 金额: $ 31.95万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209015/
• 关键词: ADAM; MMP; osteoarthritis; CD151; tissue destruction; regeneration; knockout mice; wound healing; 腫瘍浸潤・転移; 活性化; 心筋梗塞; グリオーマ; MMPインヒビター; MMP-2ノックアウトマウス; プロテアーゼ

CD151, a member of the tetraspanin family, was co-localized with MMP-7 in the chondrocytes of osteoarthritic cartilage, showing positive correlations of the CD151 immunoreactivity with Mankin scores and degree of chondrocyte cloning. Co-localization of the molecules in osteoarthritic chondrocytes resulted in pericellular activation of proMMP-7. These data suggest that CD151 is implicated in the destruction of articular cartilage and chondrocyte regeneration through the proMMP-7 activation in osteoarthritis. Among the proteinase-type ADAM8, 9, 10, 12, 15, 17, 20, 21, 28 and 30, ADAM12 was selectively expressed in the osteoarthritic chondrocytes and its immunoreactivity in osteoarthritic cartilage showed a direct correlation with degree of chondrocyte cloning. Cell proliferation and ADAM12 expression were induced by the chondrocyte treatment with TGF-β, and cell proliferation was inhibited with ADAM inhibitor, neutralizing anti-ADAM12 antibody or siRNA for ADAM12. The findings that ADAM 12 releases IGF-I from the IGF-PIGF-BP complex through digestion of IGF-BP suggest that ADAM12 is involved in chondrocyte proliferation through enhanced availability of IGF-I in osteoarthritis. Wound healing processes were analyzed in wild type, MMP-13-/-, MMP-9-/-and MMP-9/13-/-mice and compared each other. Re-epithelialization was delayed in MMP-9/13-/-, MMP-9-/-and MMP-13-/-mice compared with wild type mice in this order, and angiogenesis in the granulation tissue was retarded in MMP-9/13-/-and MMP-13-/-mice. These data suggest the important roles of both MMP-9 and MMP-13 in re-epithelialization and of MMP-13 in angiogenesis.

CD151是四叠腺苷家族的成员，在骨关节炎软骨的软骨细胞中与MMP-7共定位，显示CD151免疫反应性与人体金评分的正相关性和软骨细胞的阳性相关性。骨关节炎软骨细胞中分子的共定位导致细胞周围的Prommp-7激活。这些数据表明，通过骨关节炎的Prommp-7激活，CD151在破坏关节软骨和软骨细胞再生时暗示了CD151。在蛋白酶型ADAM8、9、10、12、15、20、21、28和30中，ADAM12在骨关节炎软骨细胞中有选择地表达，其免疫反应性在骨关节炎软骨中显示出与软骨细胞调节程度的直接相关性。通过用TGF-β的软骨细胞处理诱导细胞增殖和ADAM12表达，并用ADAM抑制剂抑制细胞增殖，中和ADAM12中和抗ADAM12抗体或siRNA。 ADAM 12通过消化IGF-BP从IGF-PIGF-BP复合物中释放IGF-I的发现表明，ADAM12通过增强骨关节炎中IGF-I的可用性参与了软骨细胞增殖。在野生型，MMP-13 - / - ，MMP-9 - / - 和MMP-9/13 - / - 小鼠中分析了伤口愈合过程，并相互比较。与野生型小鼠相比，在MMP-9/13 - / - ，MMP-9 - / - 和MMP-9 - / - 和MMP-9 - / - / - 小鼠中，重新上皮化延迟，并且在此顺序中，肉芽组织中的血管生成在MMP-9/13/13-/ - 和MMP-13 - / - / - / - / - / - 小鼠中延迟。这些数据表明，MMP-9和MMP-13在重新上皮化和MMP-13中的重要作用在血管生成中。

项目成果

Tetraspanin CD151 is expressed in osteoarthritic cartilage and is involved in pericellular activation of zymogen of matrix metalloproteinase-7 (matrilysin 1) in osteoarthritic cartilage.

四跨膜蛋白 CD151 在骨关节炎软骨中表达，并参与骨关节炎软骨中基质金属蛋白酶 7（基质溶素 1）酶原的细胞周激活。

• 发表时间: 2006
• 期刊: Arthritis Rheum. 54
• 作者: Fujita Y;Shiomi T.;Yanagimoto S.;Matsumoto H.;Toyama Y.;Okada Y.
• 通讯作者: Okada Y.

Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice.

• DOI: 10.1172/jci22304
• 发表时间: 2005-03
• 期刊: The Journal of clinical investigation
• 作者: Shin-ichiro Matsumura;S. Iwanaga;S. Mochizuki;H. Okamoto;S. Ogawa;Y. Okada

7th edition, Elsevier Saunders. Philadelphia

第七版，爱思唯尔桑德斯。

• 发表时间: 2005
• 作者: S.Inomata;N.Shijubo;S.Kon;M.Maeda;G.Yamada;N.Sato;S.Abe;T.TUede;Okada Y.
• 通讯作者: Okada Y.

Proteinases and matrix degradation.(Ed. by Harris E. D., Jr., Budd R. C., Ruddy S., Genovese M.C., Firestein G. S. and Sargent J. S. 8th edition.)

蛋白酶和基质降解。（Harris E. D., Jr.、Budd R. C.、Ruddy S.、Genovese M.C.、Firestein G. S. 和 Sargent J. S. 编辑，第 8 版。）

• 发表时间: 2007
• 作者: Seima;Kawaguchi;Tsuyoshi;Yoshimura;Yuji;Imamura;Masahiro;Miura;Yoshiyuki;Yanase;Yoshihisa;Fujii;Shogo;Okumura;Kengo;Suzuki;O. Takai;Okada Y.
• 通讯作者: Okada Y.

Chondromodulin-I maintain cardiac valvular function by preventing angiogenesis.

软骨调节蛋白-I 通过阻止血管生成来维持心脏瓣膜功能。

• 发表时间: 2006
• 期刊: Nat. Med. 12
• 作者: Yoshioka M.;Yuasa S.;Matsumoto K.;Shiomi T.;Shukunami C;Okada Y;Mukai M.;Shin H.;Yozu R.;Sata M.;Ogawa S.;Hiraki Y;Fukuda K.
• 通讯作者: Fukuda K.