Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25558817
DOI
10.1016/j.bbadis.2014.12.020
PII: S0925-4439(14)00414-1
Knihovny.cz E-resources
- Keywords
- Cartilage, Chondrocyte, Differentiation, FGFR3, Fibroblast growth factor receptor, WNT,
- MeSH
- beta Catenin genetics metabolism MeSH
- Models, Biological MeSH
- Cell Differentiation drug effects genetics MeSH
- Chondrocytes drug effects metabolism MeSH
- Cartilage cytology drug effects metabolism MeSH
- Fibroblast Growth Factors pharmacology MeSH
- Fibroblast Growth Factor 2 pharmacology MeSH
- HEK293 Cells MeSH
- Limb Buds drug effects embryology metabolism MeSH
- Microscopy, Confocal MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Low Density Lipoprotein Receptor-Related Protein-6 genetics metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Wnt3A Protein pharmacology MeSH
- Wnt Proteins genetics metabolism pharmacology MeSH
- Receptors, Fibroblast Growth Factor genetics metabolism MeSH
- Signal Transduction drug effects genetics MeSH
- Drug Synergism MeSH
- Transcriptome drug effects genetics MeSH
- Blotting, Western MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- beta Catenin MeSH
- Fibroblast Growth Factors MeSH
- Fibroblast Growth Factor 2 MeSH
- Low Density Lipoprotein Receptor-Related Protein-6 MeSH
- Lrp6 protein, mouse MeSH Browser
- Wnt3A Protein MeSH
- Wnt Proteins MeSH
- Receptors, Fibroblast Growth Factor MeSH
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.
Centre for Biomedical Image Analysis Faculty of Informatics Masaryk University Brno Czech Republic
Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Orthopaedic Surgery David Geffen School of Medicine at UCLA Los Angeles CA USA
Department of Orthopaedics Case Western Reserve University Cleveland OH USA
Institute of Animal Physiology and Genetics AS CR v v i Brno Czech Republic
Institute of Experimental Biology Faculty of Sciences Masaryk University Brno Czech Republic
Medical Genetics Institute Cedars Sinai Medical Center Los Angeles CA USA
References provided by Crossref.org
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