FGF Signaling: A Key Pathway During Skeletal Development

Receptor tyrosine kinases (RTKs) control fundamental cellular processes and their signal transduction is essential in skeletal, nervous, and vascular development. RTKs are activated by dimerization in the plasma membrane. Among the RTK family, the Fibroblast Growth Factor Receptors (FGFRs) play a crucial role in both development and ageing. They are expressed on the cell membrane and this family consists of five FGFRs (FGFR1-5). The native ligands for these receptors are the Fibroblast Growth Factor (FGF). This family is composed of 22 FGFs divided into three subfamilies (paracrine, endocrine, and intracellular subfamily). FGFs and FGFRs are widely expressed in both the appendicular the axial skeleton and skull and their interaction activates several signaling pathways to regulate various cell functions and metabolization of extracellular matrix (ECM) proteins, involved in skeletal development. Mutations in FGFR/FGF genes lead to a deregulation of the FGF/FGFR signaling and consequently to several skeletal dysplasias such as chondrodysplasia and craniosynostoses. Different therapeutic approaches are being established to target the abnormal functioning of FGF/FGFR signaling, the therapeutic strategies are various and associated with different mechanisms of actions. Recent progress in understanding the pathophysiological bases of these osteochondrodysplasias has enabled the first treatments to emerge.