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Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia
Bone Research ( IF 14.3 ) Pub Date : 2022-01-25 , DOI: 10.1038/s41413-021-00177-7
Ludovic Martin 1 , Nabil Kaci 1, 2 , Catherine Benoist-Lasselin 1 , Marine Mondoloni 1 , Suzanne Decaudaveine 1 , Valentin Estibals 1 , Maxence Cornille 1 , Léa Loisay 1 , Justine Flipo 1 , Benoît Demuynck 1 , Maria de la Luz Cádiz-Gurrea 3, 4 , Florent Barbault 5 , Salvador Fernández-Arroyo 3, 6 , Laurent Schibler 7 , Antonio Segura-Carretero 3, 4 , Emilie Dambroise 1 , Laurence Legeai-Mallet 1
Affiliation  

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.



中文翻译:

可可树通过调节软骨发育不全小鼠模型中的纤毛发生缺陷来改善骨骼生长

成纤维细胞生长因子受体 3 基因 ( FGFR3 ) 的功能获得性突变导致软骨发育不全 (ACH),这是最常见的侏儒症形式。FGFR3 的组成型激活损害骨形成和伸长以及许多信号转导途径。鉴定靶向 FGFR3 信号通路的新的和相关的化合物对于治疗 ACH 具有广泛的重要性,而天然植物化合物是主要的候选药物来源。在这里,我们发现从可可树中分离出的酚类化合物 (-)-表儿茶素可有效抑制 FGFR3 的下游信号通路。Fgfr3中的转录组分析小鼠模型显示睫状体 mRNA 表达受到印度刺猬和 PKA 途径的显着改变和影响。(-)-表儿茶素能够挽救控制初级纤毛结构组织和纤毛发生相关基因的 mRNA 表达障碍。在从 ACH 小鼠模型 ( Fgfr3 Y367C/+ ) 分离的股骨中,我们发现 (-)-表儿茶素在 6 天的离体培养过程中消除了骨生长障碍。在体内,我们证实每天将 (-)-表儿茶素皮下注射到Fgfr3 Y367C/+小鼠增加了骨伸长率并挽救了在软骨细胞中观察到的原发性纤毛缺陷。这种对初级纤毛的修饰促进了扁平增殖软骨细胞的典型柱状排列,从而增强了骨伸长率。目前的原理验证研究结果支持 (-)-表儿茶素作为治疗 ACH 的潜在药物。

更新日期:2022-01-25
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