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Review
. 2021 Nov 24:9:764781.
doi: 10.3389/fcell.2021.764781. eCollection 2021.

An Overview of in vivo Functions of Chondroitin Sulfate and Dermatan Sulfate Revealed by Their Deficient Mice

Affiliations
Review

An Overview of in vivo Functions of Chondroitin Sulfate and Dermatan Sulfate Revealed by Their Deficient Mice

Shuji Mizumoto et al. Front Cell Dev Biol. .

Abstract

Chondroitin sulfate (CS), dermatan sulfate (DS) and heparan sulfate (HS) are covalently attached to specific core proteins to form proteoglycans in their biosynthetic pathways. They are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases as well as sulfotransferases. Structural diversities of CS/DS and HS are essential for their various biological activities including cell signaling, cell proliferation, tissue morphogenesis, and interactions with a variety of growth factors as well as cytokines. Studies using mice deficient in enzymes responsible for the biosynthesis of the CS/DS and HS chains of proteoglycans have demonstrated their essential functions. Chondroitin synthase 1-deficient mice are viable, but exhibit chondrodysplasia, progression of the bifurcation of digits, delayed endochondral ossification, and reduced bone density. DS-epimerase 1-deficient mice show thicker collagen fibrils in the dermis and hypodermis, and spina bifida. These observations suggest that CS/DS are essential for skeletal development as well as the assembly of collagen fibrils in the skin, and that their respective knockout mice can be utilized as models for human genetic disorders with mutations in chondroitin synthase 1 and DS-epimerase 1. This review provides a comprehensive overview of mice deficient in CS/DS biosyntheses.

Keywords: chondroitin sulfate; dermatan sulfate; epimerase; glycosyltransferase; knockout mouse; proteoglycan; sulfotransferase; transporter.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Typical repeating disaccharide units in CS and DS. CS consists of GlcA and GalNAc, whereas DS is a stereoisomer of CS including IdoA instead of GlcA. These sugar moieties are esterified by sulfate at various positions, as indicated in the figures.
FIGURE 2
FIGURE 2
Biosynthetic assembly of CS and DS backbones by various glycosyltransferases. Schematic presentation of the biosynthesis of CS and DS backbones. All glycosyltransferases require a corresponding UDP-sugar, such as UDP-Xyl, -Gal, -GlcA, and -GalNAc, as a donor substrate. After specific core proteins have been translated, synthesis of the common GAG-protein linkage region, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-, is evoked by XylT, which transfers a Xyl residue from UDP-Xyl to the specific serine residue(s) at the GAG attachment sites. The linker region tetrasaccharide is subsequently constructed by GalT-I, GalT-II, and GlcAT-I. The first β1-4-linked GalNAc residue is then transferred to the GlcA residue in the linker region by GalNAcT-I, which initiates the assembly of the chondroitin backbone, thereby resulting in the formation of the repeating disaccharide region, [-4GlcAβ1-3GalNAcβ1-]n, by CS-polymerase. DS-epimerase converts GlcA into IdoA by epimerizing the C-5 carboxy group in the chondroitin precursor, thereby resulting in the formation of the repeating disaccharide region of dermatan precusor, [-4IdoAα1-3GalNAcβ1-]n. Each enzyme and its coding gene are described under the respective sugar symbols.
FIGURE 3
FIGURE 3
Modification of CS and DS by sulfotransferases and epimerases. Modification pathways of CS and DS. After formation of the CS/DS backbones, each sugar residue is modified by sulfation, catalyzed by sulfotransferases, as indicated in the figure. C4ST or C6ST transfers a sulfate group from PAPS to the C-4 or C-6 position of the GalNAc residues in the chondroitin chain, respectively. D4ST transfers a sulfate group from PAPS to the C-4 position of the GalNAc residues in dermatan. Further sulfation reactions are catalyzed by GalNAc4S-6ST or UST, which is required for formation of the disulfated disaccharide units indicated, respectively.

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