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

作　　者：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 

机构地区：[1]Universitéde Paris,Imagine Institute,Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia,INSERM UMR 1163,F‑75015,Paris,France [2]Inovarion,Paris,France [3]Department of Analytical Chemistry,University of Granada,Granada,Spain [4]Research and Development of Functional Food Centre(CIDAF),Granada,Spain [5]Universitéde Paris,ITODYS,CNRS,UMR 7086,15 rue J-A de Baïf,Paris,France [6]Biomedical Research Unit,Medicine and Surgery Department,Rovira i Virgili University,Tarragona,Spain [7]ALLICE,Maison Nationale des Eleveurs,Paris,France

出　　处：《Bone Research》2022年第1期137-149,共13页骨研究（英文版）

基　　金：This program received a state subsidy managed by the National Research Agency under the “Investments for the Future” Program bearing the reference ANR-10-IAHU-01;Some of the work presented here was funded by the European Community’s Seventh Framework Program under grant agreement 602300 (the SYBIL program (https://www.sybil-fp7.eu/) is funded by the MRC (MC_UU_000007/9))

摘　　要：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(Fgfr3^(Y367C/+))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 Fgfr3^(Y367C/+) 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.

关 键 词：inhibited arrangement eliminated 

分 类 号：R681.3[医药卫生—骨科学]