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Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model
Davide Komla-Ebri, … , Martin Biosse-Duplan, Laurence Legeai-Mallet
Davide Komla-Ebri, … , Martin Biosse-Duplan, Laurence Legeai-Mallet
Published April 11, 2016
Citation Information: J Clin Invest. 2016;126(5):1871-1884. https://doi.org/10.1172/JCI83926.
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Research Article Bone biology

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

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Abstract

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.

Authors

Davide Komla-Ebri, Emilie Dambroise, Ina Kramer, Catherine Benoist-Lasselin, Nabil Kaci, Cindy Le Gall, Ludovic Martin, Patricia Busca, Florent Barbault, Diana Graus-Porta, Arnold Munnich, Michaela Kneissel, Federico Di Rocco, Martin Biosse-Duplan, Laurence Legeai-Mallet

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Figure 1

NVP-BGJ398 inhibits the activation of FGFR3 and rescues ex vivo bone growth of Fgfr3Y367C/+ mouse embryo femurs.

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NVP-BGJ398 inhibits the activation of FGFR3 and rescues ex vivo bone gro...
(A) Phosphorylated FGFR3 expression in transfected human chondrocytes with FGFR3 (WT), FGFR3G380R (ACH), FGFR3Y373C (TDI), and FGFR3K650E (TDII) constructs. (B) Phosphorylated FGFR3 expression in transfected HEK293-Vnr cells with FGFR3 (WT), FGFR3Y373C (TDI), and FGFR3K650M (SADDAN) constructs. Lanes were run on the same gel, but were noncontiguous. (C) Gain of length of E16.5 femurs in culture for 6 days (ΔD6-D0) with or without treatment (Fgfr3+/+, n = 6; untreated Fgfr3Y367C/+, n = 6; 10 nM Fgfr3Y367C/+, n = 5; 100 nM Fgfr3Y367C/+, n = 6; Fgfr3Y367C/+, n = 8. *P < 0.05, 1-way ANOVA. Scale bar: 1 mm. (D) H&E staining and immunohistochemistry for Col X and Ki67 on embryonic distal femur following 6 days of culture with or without treatment. Arrows indicate hypertrophic area. Scale bars: 200 μm. (E) Number of Ki67-labeled cells in treated and untreated Fgfr3Y367C/+ compared with Fgfr3+/+ embryonic femur (n = 6 per group). *P < 0.05, 1-way ANOVA. (F) Col X–labeled growth plate area in Fgfr3+/+ and Fgfr3Y367C/+ treated and untreated embryonic femur (n = 5 per group). *P < 0.05, 1-way ANOVA. Western blots are representative of 3 independent experiments. Data are expressed as mean ± SD.

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