Macrophage-Specific Overexpression of Human Matrix Metalloproteinase-12 in Transgenic Rabbits |
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Authors: | Fan Jianglin Wang Xiaofei Wu Lihua Matsumoto Shin-Ich Liang Jingyan Koike Tomonari Ichikawa Tomonaga Sun Huijun Shikama Hisataka Sasaguri Yasuyuki Watanabe Teruo |
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Institution: | Laboratory of Cardiovascular Disease, Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8575, Japan. j-lfan@md.tsukuba.ac.jp |
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Abstract: | Increased matrix metalloproteinase-12 (MMP-12) has been implicated in atherosclerosis and many other inflammatory processes.
To define MMP-12 functions in vivo, we generated transgenic rabbits that expressed human (h) MMP-12 gene under the control of a macrophage-specific promoter,
the human scavenger receptor promoter. Two transgenic founder rabbits were found to have hMMP-12 transgene integration by
Southern blot analysis. hMMP-12 mRNA was expressed in peritoneal and alveolar macrophages, and in tissues enriched in macrophages
in transgenic rabbits. High levels of hMMP-12 protein were detected in the conditioned media of cultured peritoneal and alveolar
macrophages from transgenic rabbits. Zymography showed that hMMP-12 secreted from macrophages possessed enzymatic activity
toward β-casein. To evaluate the expression of hMMP-12 in inflammatory sites, we used carrageenan-induced granulomas as an
in vivo model for tissue macrophages and foam cells. Granuloma size in transgenic rabbits was significantly increased compared to
that in control rabbits, and histological examination revealed that granulomas of transgenic rabbits were enriched in macrophages
associated with increased hMMP-12 expression. We believe that this transgenic rabbit model with increased expression of hMMP-12
may become a useful model for further mechanistic studies of MMP-12 in inflammatory diseases and cancer invasion; it is also
an ideal model for testing the in vivo action of MMP-12 inhibitors. |
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Keywords: | atherosclerosis carrageenan-granuloma inflammation macrophage MMPs transgenic rabbits |
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