Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix

Human glomerular mesangial cells (HMC) are embedded in the mesangial matrix (MM) and control its turnover through a dynamic equilibrium between synthe sis and degradation. Degradation is controlled by matrix metalloproteinases (MMP), whose activity has been causally implicated in the progression of g lomerular disease. In other systems, MMP secretion may be directly affected by exposure to specific matrix proteins. The present study, therefore, inv estigated the effect of different matrix components on the adherence of HMC and on their secretion and activation of the gelatinases MMP2 and MMP9. HM C adhered strongly (quantified using crystal violet staining) to collagen I V and collagen I (P < 0.01, relative to binding to control, bovine serum al bumin (BSA)-coated wells) and to a lesser extent to gelatin IV and fibronec tin (P < 0.05). Binding to vitronectin and laminin was not statistically di fferent to control wells. After the addition of these matrix proteins (0.1 mug/ml to 100 mug/ml) to growth-arrested HMC for 72 h, zymography of the co nditioned medium established that only fibronectin and collagens I and IV d ose-dependently increased latent (72 kD) MMP2 secretion and activation. Fib ronectin, however, also induced the secretion of MMP9. Membranes from HMC t hat had been cocultured with fibronectin for 72 h were prepared to investig ate whether the activation of MMP2 in this system was due to the action of membrane-type (MT)-MMP. When incubated with latent MMP2 for times up to 24 h, these membranes activated the enzyme in a time- and dose-dependent manne r. The results demonstrate that specific matrix components increased the se cretion of MMP2 and MMP9 from HMC. In addition, MT-MMP activity, selectivel y induced by fibronectin, was implicated in the activation of the secreted proteinases.