Disruption of the Fgfr1-Fgf23-Phosphate Axis and Targeted Therapy in a Murine Model of Osteoglophonic Dysplasia

Osteoglophonic Dysplasia (OGD) is an autosomal dominant skeletal dysplasia characterized by impaired bone growth resulting in short stature, severe craniofacial abnormalities, and in some patients FGF23-mediated hypophosphatemia. It is caused by gain-of-function variants in FGFR1, particularly in or near the transmembrane domain of the receptor. We used CRISPR to knock-in the Fgfr1 p.N330I variant in mice, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Fgfr1+/N330I model demonstrated markedly small body weight, nasoanal length, shortened long bones, and craniosynostosis, all hallmarks of the human disease. Mutant mice exhibited profound microarchitectural changes in cortical bone and severe disorganization of the growth plate and articular cartilage, driven by decreased cell proliferation and increased apoptosis in skeletal tissues. Other than the osteochondrodysplasia, we noted dramatic increases in plasma FGF23 and hypophosphatemia, driven by upregulated Fgf23 mRNA expression and protein levels in bone, with consequent undermineralization. An in vivo ossicle assay allowed longitudinal evaluation of mineral metabolism. We attempted to modulate the signaling pathway by repurposing an inhibitor of the overactive receptor, infigratinib, resulting in partial restoration of length in treated mutant mice. These data offer insights into the pathogenesis of OGD and open avenues for potential targeted therapeutic strategies. Overall design: Trancriptomics of RNA extracted from femurs collected from 3- or 4-week-old mice (5 Fgfr1+/N330I mice and 5 WT littermate controls).