Fibroblast growth factor (FGF) signaling in development and skeletal diseases

Abstract

Fibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development.

Keywords: Craniosynostosis; FGF signaling; Fibroblast growth factor; Fibroblast growth factor receptor; Genetics; Pathogenesis; Signal transduction; Skeletal development.

Figure 1

FGF-FGFR signaling pathway. The signaling cascade commences upon the formation of an FGF binding complex, consisting of two FGF ligands, two heparin sulfate chains, and two FGFRs. Signal transduction largely follows one of three pathways. The RAS/MAP kinase pathway, initiated upon the formation of an FRS2 complex, controls cell proliferation and differentiation. The PI3/AKT pathway is also initiated by the formation of an FRS2 complex, and regulates cell survival and fate determination. Finally, upon binding of PLCγ to the activated FGFR, DAG and IP3 are formed, activating PKC. The PLCγ pathway influences cell morphology, migration, and adhesion.

Figure 2

Schematic representation of developing coronal suture. In the presence of low concentrations of FGF2, undifferentiated osteoprogenitor cells expressing FGFR2 and FGFR3 proliferate within the suture mesenchyme between the two osteogenic fronts. At higher levels of FGF2, osteoprogenitor cells are recruited to differentiate into osteoblasts. This leads to increased of FGFR1 expression and deposition of osteoid matrix along the osteogenic fronts.