2. Academic Validation
  3. Disruption of the FGFR1-FGF23-Phosphate Axis and Targeted Therapy in a Murine Model of Osteoglophonic Dysplasia

Disruption of the FGFR1-FGF23-Phosphate Axis and Targeted Therapy in a Murine Model of Osteoglophonic Dysplasia

  • bioRxiv. 2025 Nov 14:2025.11.14.680268. doi: 10.1101/2025.11.14.680268.
Giuliana Ascone 1,  Rajdeep Kaur 2,  Arwaa Mehran 2,  Cecilia Rivas 3,  Rebeca Galisteo 4,  Irene Ginty 5,  Shanna Cloud 3,  Arthur MacLarty 5,  Li Li 6,  Gene Elliot 3,  Mara Riminucci 7,  Alessandro Corsi 7,  Dawn E Watkins-Chow 8,  Lisa Garrett 3,  Iris R Hartley 4,  Luis Fernandez de Castro 4,  Carlos R Ferreira 2
Affiliations

Affiliations

  • 1 Marseille Medical Genetics (MMG), Aix-Marseille Université (AMU), Marseille, France.
  • 2 Unit on Skeletal Genomics Unit (SGU), Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA.
  • 3 Mouse Transgenic and Gene Editing Core, National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, USA.
  • 4 Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research (NIDCR), Bethesda, MD, USA.
  • 5 Office of Laboratory Animal Medicine (OLAM), National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, USA.
  • 6 NIDCR Imaging Core, National Institute of Dental and Craniofacial Research (NIDCR), Bethesda, MD, USA.
  • 7 Department of Molecular Medicine, Sapienza University of Rome, Viale Regina 324, 00161 Rome, Italy.
  • 8 Section on Mammalian Development and Evolution, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA.
PMID: 41473314 DOI: 10.1101/2025.11.14.680268
Abstract

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 in mice to knock-in the FGFR1 p.N330I variant, chosen based on its association with FGF23 excess. Skeletal phenotyping of this Fgfr1 +/N330I model demonstrated markedly reduced body weight and naso-anal 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. In addition to osteochondrodysplasia, we noted dramatic increases in plasma FGF23 and hypophosphatemia, driven by upregulated Fgf23 expression and protein levels in bone, with consequent undermineralization. An in vivo ossicle assay allowed longitudinal evaluation of mineral metabolism. We modulated the signaling pathway by repurposing an inhibitor of the overactive receptor, infigratinib, resulting in partial restoration of naso-anal length in treated mutant mice. This first model of OGD offers insights into the disease pathogenesis and open avenues for targeted therapeutic strategies.

Figures
Products