Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia

Abstract

A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. The constitutive activation of FGFR3 impaired bone formation and elongation and many signaling transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH. Natural plant compounds are the prime sources of drug candidates. Here, we found that the phenol compound (-)-epicatechin isolated from Theobroma cacao effectively inhibits FGFR3s downstream signaling pathways. Transcriptomic analysis in 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 impairments in the expression of these mRNA 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 countered the bone growth impairment during 6 days of ex vivo cultures. We confirmed in vivo that daily subcutaneous injections of (-)-epicatechin in Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defect observed in chondrocytes. This modification of 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 illustrated (-)-epicatechins ability may facilitate the development of (-)-epicatechin as a treatment for patients with ACH.