Skip to main content
Fig. 13 | Molecular Medicine

Fig. 13

From: Tamoxifen and bone morphogenic protein-7 modulate fibrosis and inflammation in the peritoneal fibrosis model developed in uremic rats

Fig. 13

Schematic representation of the TGF-ß/Smad signalling pathway and the possible targets of tamoxifen (TAM) and rBMP7 to prevent PF development. TGF-ß1 binds to the transmembrane serine/threonine kinase cell surface receptor, initiating downstream signal transduction pathways by Smad2 and Smad3 (Smad2/3). phosphorylation. Phosphorylated Smad2/3 forms heteromeric complexes with Smad4, which translocate to the nucleus to regulate the transcription of specific fibrogenic genes, and of Smad7, an intracellular antagonist of TGFβ/Smad signaling. Smad7 interacts with TGF-ß type I receptors, thereby causing receptor ubiquitination and degradation and inhibiting Smad2/3 phosphorylation. Therefore, phosphorylated Smad2/3 interaction with Smad4 is inhibited, providing a negative autoregulation of TGF-ß/Smad signaling. TAM binds to ER-α, which interacts with Smad3, preventing Smad3 phosphorylation. Blocking Smad3 phosphorylation halts downstream TGF-ß signaling and profibrotic factors synthesis. On the other hand, TAM directly increases Smad7 expression, contributing to the negative regulation of TGF-ß signaling. rBMP7 binds to BMP receptors, promoting phosphorylation of Smad1/5/8, which form complexes with Smad4 and translocate to the nucleus to regulate the expression of specific genes. BMP7 inhibits Smad3 DNA binding and induces Smad7 expression to exert negative regulation of TGF-ß pathway. TNF-α and other proinflammatory cytokines bind to their specific cell surface receptors and promote IκBα phosphorylation, which releases both p50/p65 NFκB subunits into the cytoplasm. Phosphorylated IκBα is degraded, and the NF-KB pathway is activated, with subsequent phosphorylation of the p65 subunit, which permits translocation of the subunit to the nucleus to regulate the expression of proinflammatory genes. Smad7 can block TNF-α and other proinflammatory cytokines signaling pathways by up-regulating IκB-α, expression, thereby exerting anti-inflammatory effects

Back to article page