The Specific Role of Dermatan Sulfate as an Instructive Glycosaminoglycan in Tissue Development

Abstract

The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers–Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade.

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome

“…from UDP-Gal to Xyl-O-Ser in the core proteins of PGs in the Golgi apparatus [37,4 GalT-I interacts with XylT, which has been demonstrated through co-immunoprec tion and the course purification of GalT-I [50,51]. B3GALT6 encodes β1,3-galactosyl ferase-II (GalT-II), which transfers a β3Gal moiety from UDP-Gal to Galβ1-4Xylβ1in the core proteins of PGs [45,46,52].…”

“…Dermatan sulfate (DS) is classified as a sulfated glycosaminoglycan (GAG) that is a linear polysaccharide chain, and it is covalently attached to the core proteins of proteoglycans (PGs) [1][2][3][4][5]. DS was first isolated from porcine skin by Karl Meyer in the 1940s [6].…”

“…The repeating disaccharide region of DS is covalently bound to the serine (Ser) residue of a specific core protein through the common GAGlinker region tetrasaccharide, glucuronic acidβ1-3galactoseβ1-3galactoseβ1-4xyloseβ1-O-Ser (GlcUA-Gal-Gal-Xyl-O-Ser) [22][23][24][25][26][27] (Figure 1). DS-PGs encompassing DS side chains control a wide range of biological functions including the signal transduction via binding to effector proteins, anti-coagulation, wound healing, and assembly of extracellular matrices [2][3][4][5][28][29][30][31][32][33][34][35]. Thus, DS side chains on PGs are essential for normal development as well as the maintenance of fundamental biological functions.…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…KS has neuroregulatory properties [ 7 , 15 , 48 ], CS also has cell directive properties in neural crest cell migration and development of the notochord, neural tube, and neural networks [ 49 ] but generally is ascribed weight bearing properties as a component of aggrecan the major CS-PG of weight bearing tissues [ 50 , 51 ]. CS and the related GAG dermatan sulfate (DS) also have cell instructive properties [ 52 , 53 , 54 , 55 ]. These GAGs complement the biodiverse properties of HS.…”

Qualitative and quantitative analyses in sulfated glycosaminoglycans, chondroitin sulfate/dermatan sulfate, during 3T3‐L1 adipocytes differentiation

“…In addition, investigations of their biological roles at the cellular and molecular levels have also been carried out progressively. CS/DS is essential for the maintenance of cell proliferation and differentiation (Izumikawa et al, 2014; Mizumoto & Yamada, 2021, 2022; Ogura et al, 2021; Sirko et al, 2007; Volpi et al, 1993). Furthermore, the fluctuation of CS levels during cell differentiation may provide essential information for a better understanding of cell and tissue development.…”