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

M. Buchtova, V. Oralova, A. Aklian, J. Masek, I. Vesela, Z. Ouyang, T. Obadalova, Z. Konecna, T. Spoustova, T. Pospisilova, P. Matula, M. Varecha, L. Balek, I. Gudernova, I. Jelinkova, I. Duran, I. Cervenkova, S. Murakami, A. Kozubik, P. Dvorak,...

. 2015 ; 1852 (5) : 839-50. (Complete edition) [pub] 20150102

Language English Country Netherlands

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc16000409

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.

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$a Fibroblast growth factor and canonical WNT/β-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage / $c M. Buchtova, V. Oralova, A. Aklian, J. Masek, I. Vesela, Z. Ouyang, T. Obadalova, Z. Konecna, T. Spoustova, T. Pospisilova, P. Matula, M. Varecha, L. Balek, I. Gudernova, I. Jelinkova, I. Duran, I. Cervenkova, S. Murakami, A. Kozubik, P. Dvorak, V. Bryja, P. Krejci,
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$a 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.
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$a Oralova, Veronika $u Institute of Animal Physiology and Genetics AS CR, v.v.i., Brno, Czech Republic.
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$a Masek, Jan $u Institute of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic.
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$a Ouyang, Zhufeng $u Department of Orthopaedics, Case Western Reserve University, Cleveland, OH, USA.
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$a Obadalova, Tereza $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Varecha, Miroslav $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Duran, Ivan $u Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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$a Cervenkova, Iveta $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Murakami, Shunichi $u Department of Orthopaedics, Case Western Reserve University, Cleveland, OH, USA.
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$a Kozubik, Alois $u Institute of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic; Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i., Brno, Czech Republic.
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$a Dvorak, Petr $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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$a Bryja, Vitezslav $u Institute of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic; Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i., Brno, Czech Republic.
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$a Krejci, Pavel $u Institute of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic. Electronic address: krejcip@med.muni.cz.
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