Targeting of Proteoglycan Synthesis Pathway: A New Strategy to Counteract Excessive Matrix Proteoglycan Deposition and Transforming Growth Factor-beta 1-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-beta 1 (TGF-beta 1) 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-beta 1 in lung fibroblasts. Here, we showed that 4-MU4-deoxy-beta-D-xylopyranoside, a competitive inhibitor of beta 4-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-beta 1-induced synthesis of PGs, activation of fibroblast proliferation and fibroblast-myofibroblast differentiation. Mechanistically, 4-MU4-deoxy-xyloside treatment inhibited TGF-beta 1-induced activation of canonical Smads2/3 signaling pathway in lung primary fibroblasts. The knockdown of beta 4-galactosyltransferase7 mimicked 4-MU4-deoxy-xyloside effects, indicating selective inhibition of beta 4-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.
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PLoS ONE, Public Library of Science, 2016, 11 (1), 〈10.1371/journal.pone.0146499〉
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Soumis le : mercredi 1 février 2017 - 17:56:13
Dernière modification le : mardi 10 juillet 2018 - 13:24:01

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Irfan Shaukat, Lydia Barre, Narayanan Venkatesan, Dong Li, Jean-Claude Jaquinet, et al.. Targeting of Proteoglycan Synthesis Pathway: A New Strategy to Counteract Excessive Matrix Proteoglycan Deposition and Transforming Growth Factor-beta 1-Induced Fibrotic Phenotype in Lung Fibroblasts. PLoS ONE, Public Library of Science, 2016, 11 (1), 〈10.1371/journal.pone.0146499〉. 〈hal-01452310〉

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