Bone morphogenetic protein 2 inhibits platelet-derived growth factor-induced c-fos gene transcription and DNA synthesis in mesangial cells - Involvement of mitogen-activated protein kinase

Bone morphogenetic proteins (BMPs) play an important role in nephrogenesis. The biologic effect and mechanism of action of these proteins in the adult kidney has not yet been studied. We investigated the effect of BMP2, a mem ber of these growth and differentiation factors, on mitogenic signal transd uction pathways induced by platelet-derived growth factor (PDGF) in glomeru lar mesangial cells. PDGF is a growth and survival factor for these cells i n vitro and in vivo. Incubation of mesangial cells with increasing concentr ations of BMP2 inhibited PDGF-induced DNA synthesis in a dose-dependent man ner with maximum inhibition at 250 ng/ml. Immune complex tyrosine kinase as say of PDGF receptor beta immunoprecipitates from lysates of mesangial cell s treated with PDGF showed no inhibitory effect of BMP2 on PDGF receptor ty rosine phosphorylation, This indicates that the inhibition of DNA synthesis is likely due to postreceptor events. However, BMP2 significantly inhibite d PDGF-stimulated mitogen-activated protein kinase (MAPK) activity that pho sphorylates the Elk-1 transcription factor, a component of the ternary comp lex factor. Using a fusion protein-based reporter assay, we also show that BMP2 blocks PDGF-induced Elk-1-mediated transcription. Furthermore, we demo nstrate that BMP2 inhibits PDGF-induced transcription of c-fos gene, a natu ral target of Elk-1 that normally forms a ternary complex that activates th e serum response element of the c-fos gene. These data provide the first ev idence that in mesangial cells, BMP2 signaling cross-talks with MAPK-based transcriptional events to inhibit PDGF-induced DNA synthesis. One target fo r this inhibition is the early response gene c-fos.