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¹ Division of Cancer Cell Research, and
² Laboratory of Gene Expression and Regulation, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, 108-8639 Japan

The biological functions of membrane-type 4 matrix metalloproteinase (MT4-MMP/MMP-17) are poorly understood because of the lack of a sensitive system for tracking its expression in vivo. We established a mutant mouse strain (Mt4-mmp^–/–) in which Mt4-mmp was replaced with a reporter gene encoding ß-galactosidase (LacZ). Mt4-mmp^–/– mice had normal gestations, and no apparent defects in growth, life span and fertility. Using LacZ as a marker, we were able to monitor the expression and promoter activity of Mt4-mmp for the first time in vivo. The tissue distribution of Mt4-mmp mRNA correlated with LacZ expression, and we showed that Mt4-mmp is expressed primarily in cerebrum, lung, spleen, intestine and uterus. We identified LacZ-positive neurons in the cerebrum, smooth muscle cells in the intestine and uterus, and macrophages located in the lung alveolar or intraperitoneal space. Contrary to the reported role of MT4-MMP as a tumor necrosis factor- (TNF-) sheddase, the lipopolysaccharide (LPS)-induced release of TNF- from Mt4-mmp^–/– macrophages was similar to that in wild-type cells, and expression of Mt4-mmp mRNA was repressed following LPS stimulation. Thus, we have established a mutant mouse strain for analyzing the physiological functions of MT4-MMP, which also serves as a sensitive system for monitoring and tracking the expression of MT4-MMP in vivo.

^* Correspondence: E-mail: mseiki{at}ims.u-tokyo.ac.jp