The function of fibroblast growth factor receptor 2 during skeletal development and pathogenesis

Fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling plays important roles during skeletal development. Fgfrs 1–3 are differentially expressed throughout developing bone. Fgfr1 and 2 are expressed by osteoblasts in the perichondrium/periosteum and Fgfr3 is expressed by proliferating chondrocytes in the growth plate. The importance has also been illustrated by genetic studies of human skeletal disorders. Human chondrodysplasia and craniosynostosis syndromes, result from activating or neomorphic mutations FGFR 1–3.; Apert syndrome (AS) is one of the most severe craniosynostosis syndrome and is associated with severe syndactyly of the hands and feet. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking immunoglobulin-like (Ig-like) domains II and III of FGFR2. AS mutations were introduced into the the full-length Fgfr2 cDNA and the function of AS mutant FGFR2 was examined in vitro. The results showed that AS mutations eliminated Fgfr2 splice form-specific ligand-binding specificity, which is essential for the paracrine signaling between epithelium and mesenchyme. The data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2.; To address the role of FGFR2 in normal bone development, a conditional gene deletion approach was adopted to overcome the early embryonic lethality of homozygous null mutations in Fgfr2. Inactivation of a floxed Fgfr2 allele with Dermol-CRE, which disrupted Fgfr2 in the osteoblast lineage, resulted in mice with skeletal dwarfism and decreased bone density. Although differentiation of the osteoblast lineage was not disturbed, the proliferation of osteoprogenitors and the anabolic function of mature osteoblasts were severely affected. These studies demonstrate that the osteoblast lineage requires multiple effectors to fulfill their function in bone formation.