THROMBOSPONDIN MODULATES ADHESION, PROLIFERATION AND PRODUCTION OF EXTRACELLULAR-MATRIX IN MESANGIAL CELLS

Thrombospondin (TSP) is produced by glomerular mesangial cells and one of the extracellular matrix in the mesangium, whereas the physiologic al role of TSP in mesangial cells is poorly understood. In order to kn ow whether TSP modulates mesangial cell functions, we investigated the effects of TSP on cell adhesion, proliferation, synthesis of extracel lular matrix and serine proteinases in cultured human mesangial cells. The substratum of TSP inhibited cell attachment and spreading in a TS P-dose-dependent manner in mesangial cells. Soluble TSP (50 mu g/ml) a lso caused the detachment of fully adherent mesangial cells, whereas T SP less than 10 mu g/ml did not. [H-3]-thymidine incorporation into me sangial cells was dose-dependently reduced by TSP. On the other hand, the production of both fibronectin and type IV collagen from mesangial cells was enhanced by TSP. The incubation of mesangial cells with TSP increased the secretion of tissue-type plasminogen activator (tPA) an d urokinase-type plasminogen activator (uPA), while plasminogen activa tor inhibitor-type 1 (PAI-1) decreased. These observations indicate th at TSP inhibits cell adhesion and proliferation in cultured human mesa ngial cells. It is also suggested that TSP influences the metabolism o f mesangial matrix by modulating both synthesis and degradation of mat rix components. Thus, TSP may be an important mediator of mesangial ce ll functions in an autocrine fashion.