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Typical repeating disaccharide units in dermatan sulfate (DS) and chondroitin sulfate (CS), and their potential sulfation sites. The DS backbone consists of L-iduronic acid (IdoUA) and N-acetyl-D-galactosamine (GalNAc), whereas CS is a stereoisomer of DS that includes D-glucuronic acid (GlcUA) instead of IdoUA. These sugar moieties may be esterified by sulfate at various positions indicated by the circled 'S'.
Source publication
The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and biglycan cause cong...
Context in source publication
Context 1
... they are ubiquitously expressed in various tissues such as brain, liver, lung, kidney and heart. DS chains consist of alternating disaccharide units comprising L-iduronic acid (IdoUA) and N-acetyl-D-galactosamine (GalNAc) residues with 50-200 repeats ( Figure 1). DS chains are modified by sulfation at the C-2 and C-4 positions on IdoUA and GalNAc residues, respectively, which is a structural fundament to a wide range of biological events involving DS such as the assembly of extracellular matrices, signal transduction through binding to growth factors, wound healing, and anti-coagulation [2,3]. ...
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Citations
... 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 GAG-linker region tetrasaccharide, glucuronic acidβ1-3galactoseβ1-3galactoseβ1-4xy-loseβ1-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. ...
Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.
... All CS/DS-biosynthetic enzymes ten Dam et al. (2007) Recent advances in studies on human genetic disorders in connective tissues have also clarified the biological significance of CS/DS side chains of PGs (Mizumoto et al., , 2017Mizumoto, 2018;Kosho et al., 2019;Malfait et al., 2020). The clinical halmarks in human diseases caused by deficiency in the biosynthetic enzymes of CS/DS are not always consistent with the phenotypes of knockout mice with deficiency of the corresponding enzymes. ...
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.
... The overexpression of chondroitin-6-sulfate in endothelial cells, which results in an imbalance of the chondroitin-6-sulfate and chondroitin-4-sulfate ratio, may be the main cause of chronic inflammatory diseases of the skin, such as skin lupus erythematosus and dermatomyositis (DM) (Kim and Werth, 2011). Defects in the core proteins of CS/DSPGs or mutations in CS/DS glycosyltransferases, epimerases, and sulfotransferases lead to a number of diseases, including congenital corneal stromal dystrophy, Meester-Loeys syndrome, and connective tissue diseases (Mizumoto et al., 2017;Kosho et al., 2019;Lautrup et al., 2020). The expression of CS/DS and DSPG is increased in a variety of fibrotic kidney diseases, including interstitial fibrosis, diabetic nephropathy, mesangial sclerosis and nephrosclerosis. ...
Chondroitin sulfate (CS) and dermatan sulfate (DS) are linear anionic polysaccharides that are widely present on the cell surface and in the cell matrix and connective tissue. CS and DS chains are usually attached to core proteins and are present in the form of proteoglycans (PGs). They not only are important structural substances but also bind to a variety of cytokines, growth factors, cell surface receptors, adhesion molecules, enzymes and fibrillary glycoproteins to execute series of important biological functions. CS and DS exhibit variable sulfation patterns and different sequence arrangements, and their molecular weights also vary within a large range, increasing the structural complexity and diversity of CS/DS. The structure-function relationship of CS/DS PGs directly and indirectly involves them in a variety of physiological and pathological processes. Accumulating evidence suggests that CS/DS serves as an important cofactor for many cell behaviors. Understanding the molecular basis of these interactions helps to elucidate the occurrence and development of various diseases and the development of new therapeutic approaches. The present article reviews the physiological and pathological processes in which CS and DS participate through their interactions with different proteins. Moreover, classic and emerging glycosaminoglycan (GAG)-protein interaction analysis tools and their applications in CS/DS-protein characterization are also discussed.
... Classic examples include congenital disorders, such as the Ehler Danlos syndrome, spondyloepimetaphyseal dysplasia, San Filippo disease, and several cancers where the DS or its conjugated protein (such as decorin, and biglycan), are upregulated. [18][19][20][21][22] Contemporary advances in microscopic modalities can provide fresh insights into physiological and pathological dynamics of fibrillar ECM topologies. ...
Collagen I, the most abundant extracellular matrix (ECM) protein in vertebrate tissues provides mechanical durability to tissue microenvironments and regulates cell function. Its fibrillogenesis in biological milieu is predominantly regulated by dermatan sulfate proteoglycans, proteins conjugated with iduronic acid‐containing dermatan sulfate (DS) glycosaminoglycans (GAG). Although DS is known to regulate tissue function through its modulation of Coll I architecture, a precise understanding of the latter remains elusive. We investigated this problem by visualizing the fibrillar pattern of fixed Coll I gels polymerized in the presence of varying concentrations of DS using second harmonic generation microscopy. Measuring mean second harmonic generation signal (which estimates the ordering of the fibrils), and surface occupancy (which estimates the space occupied by fibrils) supported by confocal reflectance microscopy, our observations indicated that the effect on fibril pattern of DS is contextual upon the latter's concentrations: Lower levels of DS resulted in sparse disorganized fibrils; higher levels restore organization, with fibrils occupying greater space. An appropriate change in elasticity as a result of DS levels was also observed through atomic force microscopy. Examination of dye‐based GAG staining and scanning electron microscopy suggested distinct constitutions of Coll I gels when polymerized with higher and lower levels of DS. We observed that adhesion of the invasive ovarian cancer cells SKOV3 decreased for lower DS levels but was partially restored at higher DS levels. Our study shows how the Coll I gel pattern‐tuning of DS is of relevance for understanding its biomaterial applications and possibly, pathophysiological functions.
... The enzyme products of EDSMC1 and EDSMC2-causing genes CHST14 and dermatansulfate epimerase (DSE) are dermatan-4-sulfotransferase-1 (D4ST1) and dermatan-sulfate epimerase, respectively. These enzymes facilitate DS biosynthesis [173,255]. D4ST1 dysfunction hinders normal production and assembly of the ECM. Additionally, disrupted ECM components, including fibronectin and fibrillar collagen types I, III, and V, have been found in D4ST1-deficient patients [74,173]. ...
Syndromic hereditary hearing impairment (HHI) is a clinically and etiologically diverse condition that has a profound influence on affected individuals and their families. As cutaneous findings are more apparent than hearing-related symptoms to clinicians and, more importantly, to caregivers of affected infants and young individuals, establishing a correlation map of skin manifestations and their underlying genetic causes is key to early identification and diagnosis of syndromic HHI. In this article, we performed a comprehensive PubMed database search on syndromic HHI with cutaneous abnormalities, and reviewed a total of 260 relevant publications. Our in-depth analyses revealed that the cutaneous manifestations associated with HHI could be classified into three categories: pigment, hyperkeratosis/nail, and connective tissue disorders, with each category involving distinct molecular pathogenesis mechanisms. This outline could help clinicians and researchers build a clear atlas regarding the phenotypic features and pathogenetic mechanisms of syndromic HHI with cutaneous abnormalities, and facilitate clinical and molecular diagnoses of these conditions.
... DS has been implicated in the development of many pathologies, such as cancer metastasis [94], connective tissue diseases [95], and inhibited neuron regeneration [96]. Research focusing on DS in tissue engineering is sparse, with the bulk of research focusing on discovery of its functions and some research focusing on DS, modified DS, and DS proteoglycans as therapeutics or as a targeting mechanism for drug delivery [97][98][99][100][101]. ...
Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions.
... A defective biosynthesis of proteoglycans carrying dermatan sulfate (PGDS) is also responsible for human skin and skeleton disorder. The disorder comes probably with a change of matrix proteins like collagen and cell signaling proteins [207]. ...
Glycoconjugates have great potential to improve human health in a multitude of different ways and fields. Prominent examples are human milk oligosaccharides and glycosaminoglycans. The typical choice for the production of homogeneous glycoconjugates is enzymatic synthesis. Through the availability of expression and purification protocols, recombinant Leloir glycosyltransferases are widely applied as catalysts for the synthesis of a wide range of glycoconjugates. Extensive utilization of these enzymes also depends on the availability of activated sugars as building blocks. Multi-enzyme cascades have proven a versatile technique to synthesize and in situ regenerate nucleotide sugar.In this chapter, the functions and mechanisms of Leloir glycosyltransferases are revisited, and the advantage of prokaryotic sources and production systems is discussed. Moreover, in vivo and in vitro pathways for the synthesis of nucleotide sugar are reviewed. In the second part, recent and prominent examples of the application of Leloir glycosyltransferase are given, i.e., the synthesis of glycosaminoglycans, glycoconjugate vaccines, and human milk oligosaccharides as well as the re-glycosylation of biopharmaceuticals, and the status of automated glycan assembly is revisited.
... Based on our studies, we have proposed a uniform autoantigenicity mechanism by which autoAgs share a common biochemical property in their affinity to dermatan sulfate (DS), and by which autoAgs forming a molecular complex with DS to induce autoreactive B cell responses [1][2][3][4][5]. DS, a glycosaminoglycan polysaccharide, is expressed most abundantly in the skin and other connective tissues [6], and its expression has been reported to increase during high cellular turnaround, such as wound healing [7][8][9]. It is possible that DS is upregulated to facilitate dead cell clearance and new cell growth for tissue regeneration. ...
Background:
Autoantibodies are a hallmark of autoimmune diseases. Autoantibody screening by indirect immunofluorescence staining of HEp-2 cells with patient sera is a current standard in clinical practice. Differential diagnosis of autoimmune disorders is based on commonly recognizable nuclear and cytoplasmic staining patterns. In this study, we attempted to identify as many autoantigens as possible from HEp-2 cells using a unique proteomic DS-affinity enrichment strategy.
Methods:
HEp-2 cells were cultured and lysed. Total proteins were extracted from cell lysate and fractionated with DS-Sepharose resins. Proteins were eluted with salt gradients, and fractions with low to high affinity were collected and sequenced by mass spectrometry. Literature text mining was conducted to verify the autoantigenicity of each protein. Protein interaction network and pathway analyses were performed on all identified proteins.
Results:
This study identified 107 proteins from fractions with low to high DS-affinity. Of these, 78 are verified autoantigens with previous reports as targets of autoantibodies, whereas 29 might be potential autoantigens yet to be verified. Among the 107 proteins, 82 can be located to nucleus and 15 to the mitotic cell cycle, which may correspond to the dominance of nuclear and mitotic staining patterns in HEp-2 test. There are 55 vesicle-associated proteins and 12 ribonucleoprotein granule proteins, which may contribute to the diverse speckled patterns in HEp-2 stains. There are also 32 proteins related to the cytoskeleton. Protein network analysis indicates that these proteins have significantly more interactions among themselves than would be expected of a random set, with the top 3 networks being mRNA metabolic process regulation, apoptosis, and DNA conformation change.
Conclusions:
This study provides a proteomic repertoire of confirmed and potential autoantigens for future studies, and the findings are consistent with a mechanism for autoantigenicity: how self-molecules may form molecular complexes with DS to elicit autoimmunity. Our data contribute to the molecular etiology of autoimmunity and may deepen our understanding of autoimmune diseases.
... The reduction of sGAGs has been described as being detrimental on the biomechanical behavior of connective tissues [64,65]; however, TRICOL decellularized scaffolds likely revealed only a tendency to an increased compliance under tensile load with respect to their original counterpart. In similar settings, this biomechanical property appeared to be strongly reduced by GA-treatment (e.g. ...
Xenogeneic pericardium-based substitutes are employed for several surgical indications after chemical shielding, limiting their biocompatibility and therapeutic durability. Adverse responses to these replacements might be prevented by tissue decellularization, ideally removing cells and preserving the original extracellular matrix (ECM). The aim of this study was to compare the mostly applied pericardia in clinics, i.e. bovine and porcine tissues, after their decellularization, and obtain new insights for their possible surgical use. Bovine and porcine pericardia were submitted to TRICOL decellularization, based on osmotic shock, detergents and nuclease treatment. TRICOL procedure resulted in being effective in cell removal and preservation of ECM architecture of both species’ scaffolds. Collagen and elastin were retained but glycosaminoglycans were reduced, significantly for bovine scaffolds. Tissue hydration was varied by decellularization, with a rise for bovine pericardia and a decrease for porcine ones. TRICOL significantly increased porcine pericardial thickness, while a non-significant reduction was observed for the bovine counterpart. The protein secondary structure and thermal denaturation profile of both species’ scaffolds were unaltered. Both pericardial tissues showed augmented biomechanical compliance after decellularization. The ECM bioactivity of bovine and porcine pericardia was unaffected by decellularization, sustaining viability and proliferation of human mesenchymal stem cells and endothelial cells. In conclusion, decellularized bovine and porcine pericardia demonstrate possessing the characteristics that are suitable for the creation of novel scaffolds for reconstruction or replacement: differences in water content, thickness and glycosaminoglycans might influence some of their biomechanical properties and, hence, their indication for surgical use.
... While the exact mechanism underlying corneal clouding remains elusive, one prominent theory involves defects in the organization of type 1 collagens. Decorin is a dermatan proteoglycan that regulates collagen fibrogenesis, and defects in the decorin gene result in diffuse corneal clouding with decreased corneal transparency [61]. ...
The mucopolysaccharidoses (MPS) are a heterogenous group of lysosomal storage disorders caused by the accumulation of glycosaminoglycans (GAGs). The accrual of these compounds results in phenotypically varied syndromes that produce multi-organ impairment with widespread systemic effects. The low incidence of MPS (approximately 1/25,000 live births) in conjunction with the high childhood mortality rate had limited the availability of research into certain clinical features, especially ocular manifestations. As the recent successes of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) have greatly increased life expectancy in these patients, they have served as a focal point for the transition of research towards improvement of quality of life. Ophthalmological findings in MPS include corneal clouding, glaucoma, optic neuropathies, and retinopathies. While corneal clouding is the most common ocular feature of MPS (especially type I, IVA, and VI), its response to HSCT and ERT is minimal. This review discusses known eye issues in the MPS subtypes, diagnosis of these ocular diseases, current clinical and surgical management, noteworthy research progress, and ultimately presents a direction for future studies.
