Skip to Content
MilliporeSigma
  • Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia.

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

Bone research (2022-01-27)
Ludovic Martin, Nabil Kaci, Catherine Benoist-Lasselin, Marine Mondoloni, Suzanne Decaudaveine, Valentin Estibals, Maxence Cornille, Léa Loisay, Justine Flipo, Benoît Demuynck, Maria de la Luz Cádiz-Gurrea, Florent Barbault, Salvador Fernández-Arroyo, Laurent Schibler, Antonio Segura-Carretero, Emilie Dambroise, Laurence Legeai-Mallet
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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-γ-Tubulin antibody, Mouse monoclonal, clone GTU-88, ascites fluid
Sigma-Aldrich
Anti-MAP Kinase (ERK-1, ERK-2) antibody produced in rabbit, whole antiserum
Sigma-Aldrich
Anti-Fibroblast Growth Factor Receptor-3, Cytoplasmic antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Actin Antibody, clone C4, ascites fluid, clone C4, Chemicon®