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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE306640 | GEO | 2025/11/20

REPOSITORIES: GEO

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Project description:We used gene array analysis of cortical bone to identify Phex-dependent gene transcripts regulating Fgf23 production and mineralization in Hyp mice. We discovered that activation of Fgf receptor- and Wnt-pathways contribute to increased Ffg23 gene transcription in Hyp bone. We found evidence in Hyp bone for increased expression of Fgf1, Fgf7, and Egr2 in the Fgf-signaling pathway and decrements in Sost and Cpz and increments in Sfrp1 and 4 in the Wnt-signaling pathway. Moreover, activation of Fgf and Wnt-signaling stimulated, whereas Tgf β inhibited Fgf23 promoter activity in osteoblasts. We also observed reductions in Bmp1, a metalloproteinase that metabolizes the Fgf23 regulatory extracellular matrix protein Dmp1. These findings suggest that elevation of Fgf23 expression in osteocytes is regulated by interactions between cell surface expression of Phex, extracellular matrix proteins and paracrine effects of Fgf and Wnt. Alterations were also found in enzymes regulating the posttranslational processing and stability of Fgf23, including decrements in the glycosyltransferase Galnt3 and the proprotein convertase Pcsk5. In addition, we found that the Pcsk5 and the glycosyltransferase Galnt3 were decreased in Hyp bone, suggesting that reduced post-translational processing of FGF23 may also contribute to increased Fgf23 levels in Hyp mice. With regards to mineralization, we identified additional candidates to explain the intrinsic mineralization defect in Hyp osteoblasts, including increases in the mineralization inhibitors Mgp and Thbs4, as well as increases in local pH altering factors, carbonic anhydrase 12 (Car12) and 3 (Car3) and the sodium-dependent citrate transporter (Slc13a5). These studies demonstrate the complexity of gene expression alterations in bone that accompanies inactivating Phex mutations and identify novel pathways that may coordinate Fgf23 expression and mineralization of extracellular matrix in Hyp bone. We isolated total RNAs from long bones of both WT and Hyp mice at 12 days of age. Since the RNA yields from the long bones are very low, we combined 2 bone samples with same genotype (WT or Hyp) for one RNA extraction. We will compare the difference of the gene expressions between Hyp and WT. We will use 4 samples in each animal condition.

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

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