Regulation of matrix degrading enzymes and their intrinsic inhibitors in renal inflammation and during tumorigenesis
Wolfgang Eberhardt (group leader), Kristina Häußler, Roswitha Müller, U. Nasrullah, S. Kusch
Remodeling of extracellular matrix (ECM) is an important feature of normal growth and developmental processes. Consequently, an imbalance of ECM synthesis and degradation is associated with many diseases, most prominently rheumatoid arthritis, fibrosis and tumor metastasis. Although changes in the synthesis of ECM may play a certain role in dysregulation of matrix turnover, recent studies have underlined the paramount role of ECM degradative systems. The main proteases regulating physiological degradation of ECM are the matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes, which include the interstitial collagenases, stromelysins, elastases, membrane-type MMPs and gelatinases A tight regulation of most of these proteases is accomplished by different mechanisms, including the regulation of MMP gene expression, the processing and conversion of the inactive zymogens by other proteases and, finally, the inhibition of active MMPs by endogenous inhibitors of MMPs, the tissue inhibitors of metalloproteinases (TIMPs). We use cultured rat mesangial cells (MC) as a model system to investigate the mechanistical details of extracellular matrix remodeling. These cells highly respond to proinflammatory cytokines such as tumor necrosis factor a (TNFa) or interleukin-1b (IL-1b) with the transcriptional upregulation of different MMPs, including MMP-9 (gelatinase-B). In addition to MMPs, MC exposed to cytokines produce high levels of NO through the expression of the inducible NO synthase (iNOS) gene.