ROLE OF THROMBOSPONDIN IN MESANGIAL CELL-GROWTH - POSSIBLE EXISTENCE OF AN AUTOCRINE FEEDBACK GROWTH CIRCUIT

Thrombospondin (TSP) is an extracellular matrix glycoprotein involved in mesangial cell (MC) adhesive and migratory function. We have studie d the role of TSP in activation and proliferation of rat MC in serum-f ree media. TSP, in a concentration dependent manner (5 to 20 mu g/ml), caused an increase in thymidine uptake, first detectable at 28 hours and more prominent at 48 hours. This effect was inhibited by heparin a nd heparan sulfate. TSP induced epidermal growth factor (EGF) secretio n and significantly augmented constitutive platelet-derived growth fac tor-AB (PDGF-AB) secretion by MC in a concentration dependent fashion. It did not, however, induce TGF-beta, IL-1, IL-6, IL-8, or TNF-alpha production. TSP had an additive effect with exogenous EGF and PDGF on thymidine uptake. Anti-PDGF neutralizing antibody eliminated the effec t of TSP on MC growth. MC displayed a single class of heparin-inhibita ble TSP binding sites (B-max 3.8 +/- 1.8 x 10(6)/cell, K-d = 80 +/- 29 nM). Based on these observations, we propose the existence of an auto crine positive feedback loop of MC proliferation involving TSP and gro wth factors, and regulated by heparan sulfate.