Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model

J Clin Invest. 2016 May 2;126(5):1871-84. doi: 10.1172/JCI83926. Epub 2016 Apr 11.


Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.

MeSH terms

  • Achondroplasia / drug therapy*
  • Achondroplasia / genetics
  • Achondroplasia / metabolism
  • Achondroplasia / pathology
  • Animals
  • Cell Line, Transformed
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Intervertebral Disc / metabolism
  • Intervertebral Disc / pathology
  • Lumbar Vertebrae / metabolism
  • Lumbar Vertebrae / pathology
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Mutant Strains
  • Phenylurea Compounds / pharmacology*
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism
  • Pyrimidines / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism*
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism


  • Phenylurea Compounds
  • Pyrimidines
  • SOX9 Transcription Factor
  • STAT1 Transcription Factor
  • Sox9 protein, mouse
  • Stat1 protein, mouse
  • infigratinib
  • Fgfr3 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 3
  • Phospholipase C gamma