Fibroblast growth factor and canonical WNT/beta-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage

Authors

BUCHTOVÁ marcela ORALOVÁ Veronika AKLIAN Anie MAŠEK Jan VESELA Iva OUYANG Zhufeng OBADALOVÁ Tereza KONEČNÁ Žaneta SPOUSTOVÁ Tereza POSPÍŠILOVÁ Tereza MATULA Petr VAŘECHA Miroslav BÁLEK Lukáš GUDERNOVÁ Iva JELÍNKOVÁ Iva DURAN Ivan ČERVENKOVÁ Iveta MURAKAMI Shunichi KOZUBÍK Alois DVOŘÁK Petr BRYJA Vítězslav KREJČÍ Pavel

Year of publication 2015
Type Article in Periodical
Magazine / Source Biochimica et Biophysica Acta - Molecular Basis of Disease
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.1016/j.bbadis.2014.12.020
Field Genetics and molecular biology
Keywords Cartilage; Chondrocyte; Differentiation; FGFR3; Fibroblast growth factor receptor; WNT
Description Aberrant fibroblast growth factor (FGF) signaling disturbs chondrocyte differentiation in skeletal dysplasia, but the mechanisms underlying this process remain unclear. Recently, FGF was found to activate canonical WNT/beta-catenin pathway in chondrocytes via Erk MAP kinase-mediated phosphorylation of WNT co-receptor Lrp6. Here, we explore the cellular consequences of such a signaling interaction. WNT enhanced the FGF-mediated suppression of chondrocyte differentiation in mouse limb bud micromass and limb organ cultures, leading to inhibition of cartilage nodule formation in micromass cultures, and suppression of growth in cultured limbs. Simultaneous activation of the FGF and WNT/beta-catenin pathways resulted in loss of chondrocyte extracellular matrix, expression of genes typical for mineralized tissues and alteration of cellular shape. WNT enhanced the FGF-mediated downregulation of chondrocyte proteoglycan and collagen extracellular matrix via inhibition of matrix synthesis and induction of proteinases involved in matrix degradation. Expression of genes regulating RhoA GTPase pathway was induced by FGF in cooperation with WNT, and inhibition of the RhoA signaling rescued the FGF/WNT-mediated changes in chondrocyte cellular shape. Our results suggest that aberrant FGF signaling cooperates with WNT/beta-catenin in suppression of chondrocyte differentiation.
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