Dermatan Sulfate Epimerase 1-Deficient Mice Have Reduced Content and Changed Distribution of Iduronic Acids in Dermatan Sulfate and an Altered Collagen Structure in Skin

Abstract

Dermatan sulfate epimerase 1 (DS-epi1) and DS-epi2 convert glucuronic acid to iduronic acid in chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the chondroitin/dermatan polysaccharide chains. The numbers of long blocks of adjacent iduronic acids are greatly decreased in skin decorin and biglycan chondroitin/dermatan sulfate, along with a parallel decrease in iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican-derived chains. DS-epi1-deficient mice are smaller than their wild-type littermates but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the chondroitin/dermatan sulfate in many proteoglycans, and the consequences for skin collagen structure were initially analyzed. We found that the skin collagen architecture was altered, and electron microscopy showed that the DS-epi1-null fibrils have a larger diameter than the wild-type fibrils. The altered chondroitin/dermatan sulfate chains carried by decorin in skin are likely to affect collagen fibril formation and reduce the tensile strength of DS-epi1-null skin.

Chondroitin/dermatan 2-O sulfotransferase potentiates Fgf2 induced cell migration

“…This underlies the importance of DS and the downstream 2-O sulfation in mediating cell migration and adhesion (Malmström et al, 2012). Notably, Dse1 2/2 mice display reduced levels of L-IdoUA blocks and DDi2,4S units and therefore might have an altered growth factor function (Maccarana et al, 2009). Interestingly, we detected DS units on the cell surface of the CHO cell lines.…”

Sequence Analysis and Domain Motifs in the Porcine Skin Decorin Glycosaminoglycan Chain

“…Indeed, a genetic mutation of human galactosyltransferase-1, which reduces both the GAG chain occupancy in decorin and the IdoA content of decorin GAG, results in connective tissue disorders (24). Furthermore, C5-epimerase-1-deficient mice showed an altered distribution of IdoA, resulting in an altered collagen structure leading to skin fragility (19,31).…”

“…Growth factor receptors, such as epidermal growth factor receptor, insulin-like growth factor receptor 1, and hepatocyte growth factor receptor are also regulated by decorin (10,31). Thus, decorin acts as a pan-tyrosine kinase receptor inhibitor (31) regulating cell growth, wound healing, angiogenesis, axon regeneration, and neural stem cell proliferation (10).…”

Iduronic Acid in Chondroitin/Dermatan Sulfate

“…IdoA can be found in blocks (stretch of ≥6 IdoA residues), in alternating IdoA/GlcA structures, or as isolated IdoA interspersed in unmodified GlcA residues ( al. 1975;Maccarana et al 2009). High content of DS epimerases, especially of DS-epi1 in vivo, and a concomitant high content of the DS-specific 4-O-sulfotransferase D4ST1 are required for formation of IdoA blocks ).…”