Role of membrane-type matrix metalloproteinase 1 (MT-1-MMP), MMP-2, and its inhibitor in nephrogenesis

Extracellular matrix (ECM) proteins, their integrin receptors, and matrix m etalloproteinases (MMPs), the ECM-degrading enzymes, are believed to be inv olved in various biological processes, including embryogenesis. In the pres ent study, we investigated the role of membrane type MMP, MT-1-MMP, an acti vator pro-MMP-2, in metanephric development. Also, its relationship with MM P-2 and its inhibitor, TIMP-2, was studied. Since mRNAs of MT-1-MMP and MMP -2 are respectively expressed in the ureteric bud epithelia and mesenchyme, they are ideally suited for juxtacrine/paracrine interactions during renal development. Northern blot analyses revealed a single similar to 4.5-kb mR NA transcript of MT-1-MMP, and its expression was developmentally regulated . Inclusion of MT-1-MMP antisense oligodeoxynucleotide (ODN) in the culture media induced dysmorphogenetic changes in the embryonic metanephros. MMP-2 antisense ODN also induced similar changes, but they were relatively less; on the other hand TIMP-2 antisense ODN induced a mild increase in the size of explants. Concomitant exposure of MT-1-MMP and MMP-2 antisense ODNs ind uced profound alterations in the metanephroi. Treatment of TIMP-2 antisense ODN to metanephroi exposed to MT-1-MMP/MMP-2 antisense notably restored th e morphology of the explants. Specificity of the MT-1-MMP antisense ODN was reflected in the selective decrease in its mRNA and protein expression. Th e MT-1-MMP antisense ODN also resulted in a failure in the activation of pr o-MMP-2 to MMP-8. These findings suggest that the trimacromolecular complex of MT-1-MMP:MMP-2:TIMP-2 modulates the organogenesis of the metanephros, c onceivably by mediating paracrine/juxtacrine epithelial:mesenchymal interac tions.