Untersuchungen zur biologischen Rolle der Matrixmetalloproteinase MMP-19

Abstract

Matrix metalloproteinases (MMP) comprise a family of extracellular matrix degrading enzymes playing pivotal roles in embryonic development and growth as well as tissue remodeling and repair. Inappropriate expression of MMP may contribute to the pathogenesis of many tissue-destructive processes, including both highly prevalent diseases such as arthritis, MS, and tooth decay, as well as the leading causes of death in developed countries: cardiovascular diseases, tumor progression, and chronic obstructive pulmonary diseases.MMP-19 had been isolated by the author as an autoantigen associated with rheumatoid arthritis called RASI-1. Phylogenetically MMP-19 seems to be an ancestral member of the MMP family. The enzymatic substrates recognized by MMP-19 may be highly specific since the domains responsible for substrate specificity in MMP-19 differ from all other MMP.MMP-19 is expressed both in blood vessels and myleoid cells. It has been shown that adhesion during myleoid differentiation leads to upregulation of MMP-19 gene expression. These and other data indicate that MMP-19 function may play a role in macrophage migration. Taken into account that MMP-19 is also expressed in smooth muscle cells MMP-19 may contribute to atherosclerotic vessel malformation.The expression of MMP-19 in micro-, but not macrovascular endothelial cells suggests that MMP-19 is a factor in early angioprocesses. Upregulation of MMP-19 mRNA levels upon angiogenetic stimuli support this view.The MMP-19 protein is not covalently attached to the surface of myeloid cells. It coprecipitates with two cell surface proteins. The attachment is mediated by the C-terminal hemopexin-like domain. In the yeast two hybrid system MMP-19 interacts with Rapa, a novel protein. Rapa does not show any significant similarity to known proteins. Primary structure analyses indicate that Rapa might contribute to cellular structures. In vitro data showed the interaction between Rapa and MMP-19.