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

Autor: Iva Vesela, Petr Dvorak, Miroslav Varecha, Vitezslav Bryja, Iveta Cervenkova, Alois Kozubík, Marcela Buchtová, Iva Jelínková, Anie Aklian, Petr Matula, Zaneta Konecna, Tereza Spoustova, Pavel Krejci, Tereza Pospisilova, Ivan Duran, Tereza Obadalova, Lukas Balek, Iva Gudernova, Shunichi Murakami, Veronika Oralova, Jan Masek, Zhufeng Ouyang
Rok vydání: 2015
Předmět:
RHOA
Fibroblast growth factor
0302 clinical medicine
Cells
Cultured
beta Catenin
0303 health sciences
Microscopy
Confocal
biology
Reverse Transcriptase Polymerase Chain Reaction
Chemistry
Wnt signaling pathway
LRP6
Cell Differentiation
Drug Synergism
LRP5
Fibroblast growth factor receptor
Cell biology
medicine.anatomical_structure
Low Density Lipoprotein Receptor-Related Protein-6
Differentiation
Molecular Medicine
Fibroblast Growth Factor 2
Signal Transduction
medicine.medical_specialty
Limb Buds
Blotting
Western
Models
Biological
Chondrocyte
WNT
03 medical and health sciences
Limb bud
Chondrocytes
Cell Line
Tumor
Wnt3A Protein
Internal medicine
medicine
Animals
Humans
Molecular Biology
030304 developmental biology
Receptors
Fibroblast Growth Factor
Rats
Fibroblast Growth Factors
Wnt Proteins
HEK293 Cells
Cartilage
Endocrinology
FGFR3
biology.protein
Transcriptome
030217 neurology & neurosurgery
Zdroj: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852:839-850
ISSN: 0925-4439
Popis: 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/β-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/β-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/β-catenin in suppression of chondrocyte differentiation.
Databáze: OpenAIRE
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