Fibrotic response in fibroblasts from congenital disorders of glycosylation.
Bottom Line: The extent of this response was confirmed at the protein level by showing increased production of collagen type-I for example.This fibrotic response of CDG fibroblasts was not paralleled by a differentiation to myofibroblasts and by increased TGF-β signalling.We could show that the addition of recombinant IGFBP5, one of the induced proteins in CDG, to healthy control fibroblasts increased the production of collagen type-I to levels similar to those found in CDG fibroblasts.
Affiliation: Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.Show MeSH
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Mentions: To appreciate the range of cellular responses linked to glycosylation disorders, we have analysed the global gene transcription profile of ALG6-CDG, DPM1-CDG and ALG12-CDG fibroblasts by oligonucleotide array hybridization . Genes with similar expression profiles in the different CDG were resolved by hierarchical clustering. This analysis showed that multiple genes encoding components of the extracellular matrix were highly induced in the three forms of CDG (Fig. 1). The induced genes comprised collagen genes such as COL1A1, COL4A1, COL4A2, COL5A1, COL11A1 and COL18A1, cartilage oligomeric protein (COMP), biglycan (BGN), hyaluronan and proteoglycan link protein 1 (HAPLN1), fibronectin (FN), tenascin-C (TNC) and nidogen-1 (NID1) in particular (Table 1). Matrix metalloproteinases, such as the BMP1 collagenase and the MMP3 proteoglycanase were also among the genes significantly overexpressed in CDG fibroblasts. Another group of ECM genes induced in CDG fibroblasts were four members of the pregnancy-specific glycoproteins (PSG). PSG are closely related to the carcinoembryonic antigen family and are mainly transcribed in the placenta , although they are also expressed in other tissues according to the UniGene’s EST Profile Viewer . Components of the TGF-β pathway were also found among the list of genes induced in CDG. The TGF-β and TGF-β receptor-I mRNAs were slightly elevated in CDG fibroblasts whereas endoglin, a co-receptor for TGF-β, was induced between 1.9- and 3.6-fold in CDG fibroblasts (Table 1). Members of the Wnt/β-catenin signalling pathway such as the Wnt2 signalling protein (WNT2), the Wnt-1 inducible signalling pathway protein (WISP-1) as well as the Sox11 transcription factor were overexpressed above twofold in CDG fibroblasts.
Affiliation: Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.