Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth

TLDR

FGFR2 signaling is essential for skeletal development, as shown by craniosynostosis syndromes and embryonic lethality of null mutants. The study aimed to determine FGFR2's role in normal bone development using a conditional deletion strategy. Conditional deletion was achieved by inserting Cre recombinase into the Dermo1 locus, driving recombination in mesenchymal condensations that generate osteoblasts and chondrocytes. Loss of FGFR2 in mesenchymal cells caused skeletal dwarfism, reduced bone density, and impaired osteoprogenitor proliferation and osteoblast anabolic activity, despite normal osteoblast differentiation.

Abstract

Human craniosynostosis syndromes, resulting from activating or neomorphic mutations in fibroblast growth factor receptor 2 (FGFR2), underscore an essential role for FGFR2 signaling in skeletal development. Embryos harboring homozygous null mutations in FGFR2 die prior to skeletogenesis. To address the role of FGFR2 in normal bone development, a conditional gene deletion approach was adopted. Homologous introduction of cre recombinase into the Dermo1 (Twist2) gene locus resulted in robust expression of CRE in mesenchymal condensations giving rise to both osteoblast and chondrocyte lineages. Inactivation of a floxed Fgfr2 allele with Dermo1-cre 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.