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.
Highlights
Pulmonary fibrosis is characterized by injury and loss of lung epithelial cells, abnormal accumulation of myofibroblasts, and excessive deposition of collagen and proteoglycans (PGs) in the extracellular matrix (ECM), resulting in a progressive loss of pulmonary function [1]
A consistent finding in animal models of lung fibrosis is an increase in the synthesis of chondroitin-sulfate/dermatan-sulfate (CS/DS) GAGs associated with accumulation of versican, a large CS-containing PG that forms macromolecular aggregates with hyaluronic acid in the interstitial matrix, and of decorin, which plays a key role in regulating collagen fibril formation and the spatial arrangement of collagen fibers in the matrix [4]
We showed that 4-MU4-deoxy-xyloside inhibited PG synthesis and counteracted Transforming growth factor-β1 (TGF-β1)-induced PG synthesis in lung fibroblasts
Summary
Pulmonary fibrosis is characterized by injury and loss of lung epithelial cells, abnormal accumulation of myofibroblasts, and excessive deposition of collagen and proteoglycans (PGs) in the extracellular matrix (ECM), resulting in a progressive loss of pulmonary function [1]. We showed recently that TGF-β1 increased PG synthesis in rat lung fibrobalasts by inducing the expression of XT-I (xylosyltransferase I) and GlcAT-I (β1, 3-glucuronyltransferase I), which regulate the rate of the PG synthesis [9] These enzymes in addition to β4Galactosyltransferase (β4GalT7) and β3Galactosyltransferase (β3GalT6) are responsible for the initiation of the synthesis of GAG chains by catalysing the formation of the linkage tetrasaccharide (GlcAβ1, 3Galβ1, 3Galβ1, 4Xylβ1-O-Ser) that attaches the GAG chain to the PG core protein. Owing to the importance of GAG chains of PGs in mediating cytokine and growth factor signaling, this strategy may attenuates TGF-β signaling and the associated profibrotic effects Xyloside analogues such as 4-Methylumbelliferyl-β-D-xylopyranoside can function as GAG chain initiators without a core protein. We bring evidence that 4-MU4-deoxy-xyloside prevented apparent fibroblast-to-myofibroblast trans-differentiation induced by TGF-β1, suggesting that inhibition of PG-GAG synthesis may provide a new therapeutic approach for IPF treatment
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