title: Targeting of Proteoglycan Synthesis Pathway: A New Strategy to Counteract Excessive Matrix Proteoglycan Deposition and Transforming Growth Factor-β1-Induced Fibrotic Phenotype in Lung Fibroblasts.
abstract: Stimulation of proteoglycan (PG) synthesis and deposition plays an important role in the pathophysiology of fibrosis and is an early and dominant feature of pulmonary fibrosis. Transforming growth factor-β1 (TGF-β1) is a major cytokine associated with fibrosis that induces excessive synthesis of matrix proteins, particularly PGs. Owing to the importance of PGs in matrix assembly and in mediating cytokine and growth factor signaling, a strategy based on the inhibition of PG synthesis may prevent excessive matrix PG deposition and attenuates profibrotic effects of TGF-β1 in lung fibroblasts. Here, we showed that 4-MU4-deoxy-β-D-xylopyranoside, a competitive inhibitor of β4-galactosyltransferase7, inhibited PG synthesis and secretion in a dose-dependent manner by decreasing the level of both chondroitin/dermatan- and heparin-sulfate PG in primary lung fibroblasts. Importantly, 4-MU4-deoxy-xyloside was able to counteract TGF-β1-induced synthesis of PGs, activation of fibroblast proliferation and fibroblast-myofibroblast differentiation. Mechanistically, 4-MU4-deoxy-xyloside treatment inhibited TGF-β1-induced activation of canonical Smads2/3 signaling pathway in lung primary fibroblasts. The knockdown of β4-galactosyltransferase7 mimicked 4-MU4-deoxy-xyloside effects, indicating selective inhibition of β4-galactosyltransferase7 by this compound. Collectively, this study reveals the anti-fibrotic activity of 4-MU4-deoxy-xyloside and indicates that inhibition of PG synthesis represents a novel strategy for the treatment of lung fibrosis.
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Irfan
authors.initials: I
authors.lastname: Shaukat
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Barré
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Narayanan
authors.initials: N
authors.lastname: Venkatesan
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: UMR 7311 CNRS-Institut de Chimie Organique et Analytique, Université d'Orléans-Pôle de Chimie, Rue de Chartres, 45067, Orléans, Cedex 02, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Jaquinet
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel-Gigleux
authors.affiliation: UMR 7365 CNRS-Université de Lorraine, Biopôle-Faculté de Médecine, CS 50184, 54505, Vandoeuvre-lès-Nancy, Cedex, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ouzzine
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003871:Dermatan Sulfate / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors; D006027:Glycosides / Q000737:chemistry; D006493:Heparin / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D009237:N-Acetyllactosamine Synthase / Q000037:antagonists & inhibitors; D010641:Phenotype; D011509:Proteoglycans / Q000096:biosynthesis*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006027:Glycosides; D036341:Intercellular Signaling Peptides and Proteins; D011509:Proteoglycans; D034741:RNA, Small Interfering; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; C036090:heparin proteoglycan; D003871:Dermatan Sulfate; D006923:Hymecromone; C014111:methylumbelliferyl-beta-D-xyloside; D006493:Heparin; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase; D009237:N-Acetyllactosamine Synthase