Extracellular BMP, PDGF, and TGF-β signaling pathways

The extracellular BMP, PDGF, and TGF-β pathways represent a complex network of signaling cascades mediated by secreted growth factors and their respective transmembrane receptors (Massagué, 2012). Bone Morphogenetic Proteins (BMPs) and Transforming Growth Factor-beta (TGF-β) belong to the TGF-β superfamily and signal primarily through serine/threonine kinase receptors and Smad transcription factors to regulate cell fate, bone formation, and tissue homeostasis (Biernacka et al., 2011). Platelet-Derived Growth Factor (PDGF) signals through receptor tyrosine kinases (PDGFR-α/β) to promote cell proliferation, migration, and angiogenesis (Andrae et al., 2008). Dysregulation of these pathways is a hallmark of various pathologies, including cancer progression, organ fibrosis, and vascular diseases like pulmonary arterial hypertension (PAH). In PAH, an imbalance between these pathways leads to pathological vascular remodeling, which can be addressed by therapeutic strategies like sotatercept, a ligand trap that restores balance in the TGF-β/BMP axis (Humbert et al., 2021). Additionally, kinase inhibitors like nintedanib target the PDGF pathway to treat fibrotic lung diseases by inhibiting fibroblast activation (Richeldi et al., 2014).

Other names

Extracellular BMP / PDGF / TGF-β pathwaysTGF-beta superfamily signalingPlatelet-derived growth factor signalingBone morphogenetic protein signalingTGF-beta/BMP/PDGF axis

Drugs targeting these pathways function through several distinct mechanisms: ligand sequestration using decoy receptors (e.g., sotatercept for TGF-β superfamily ligands), monoclonal antibodies that block ligand-receptor binding (e.g., fresolimumab), and small molecule inhibitors that target the intracellular kinase domains of the receptors (e.g., nintedanib for PDGFR) (Humbert et al., 2021; Richeldi et al., 2014).