Buchtova Marcela, Oralova Veronika, Aklian Anie, Masek Jan, Vesela Iva, Ouyang Zhufeng, Obadalova Tereza, Konecna Zaneta, Spoustova Tereza, Pospisilova Tereza, Matula Petr, Varecha Miroslav, Balek Lukas, Gudernova Iva, Jelinkova Iva, Duran Ivan, Cervenkova Iveta, Murakami Shunichi, Kozubik Alois, Dvorak Petr, Bryja Vitezslav, Krejci Pavel
Department of Anatomy, Histology and Embryology, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic; Institute of Animal Physiology and Genetics AS CR, v.v.i., Brno, Czech Republic.
Institute of Animal Physiology and Genetics AS CR, v.v.i., Brno, Czech Republic.
Biochim Biophys Acta. 2015 May;1852(5):839-50. doi: 10.1016/j.bbadis.2014.12.020. Epub 2015 Jan 2.
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.
异常的成纤维细胞生长因子（FGF）信号传导会扰乱骨骼发育不良中软骨细胞的分化，但这一过程的潜在机制仍不清楚。最近，人们发现FGF通过Erk MAP激酶介导的WNT共受体Lrp6磷酸化，在软骨细胞中激活经典的WNT/β-连环蛋白通路。在此，我们探讨这种信号相互作用的细胞后果。WNT增强了FGF在小鼠肢芽微团和肢体器官培养中对软骨细胞分化的抑制作用，导致微团培养中软骨结节形成受到抑制，以及培养肢体生长受到抑制。FGF和WNT/β-连环蛋白通路的同时激活导致软骨细胞细胞外基质丧失、矿化组织典型基因的表达以及细胞形态改变。WNT通过抑制基质合成和诱导参与基质降解的蛋白酶，增强了FGF介导的软骨细胞蛋白聚糖和胶原细胞外基质的下调。FGF与WNT协同诱导调节RhoA GTPase通路的基因表达，抑制RhoA信号传导可挽救FGF/WNT介导的软骨细胞形态变化。我们的结果表明，异常的FGF信号传导与WNT/β-连环蛋白协同抑制软骨细胞分化。
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