Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia
Metadatos
Mostrar el registro completo del ítemAutor
Martin, Ludovic; Cádiz Gurrea, María de la Luz; Fernández Arroyo, Salvador; Segura Carretero, AntonioEditorial
Nature
Fecha
2022-01-25Referencia bibliográfica
Martin, L... [et al.]. Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia. Bone Res 10, 8 (2022). [https://doi.org/10.1038/s41413-021-00177-7]
Patrocinador
French National Research Agency (ANR) ANR-10-IAHU-01; European Community - MRC 602300 MC_UU_000007/9Resumen
A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most
frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction
pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the
treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound
(-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3’s downstream signaling pathways. Transcriptomic
analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian
hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural
organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3Y367C/+) of ACH, we
showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily
subcutaneous injections of (-)-epicatechin to Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defects
observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative
chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a
potential drug for the treatment of ACH.