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

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuji Mizumoto ◽  
Shuhei Yamada
Keyword(s):  
Chondroitin Sulfate ◽  
Dermatan Sulfate ◽  
Biological Activities ◽  
Skeletal Development ◽  
Genetic Disorders ◽  
Collagen Fibrils ◽  
Comprehensive Overview ◽  
Core Proteins ◽  
Deficient Mice

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.

scholarly journals Chondroitin Sulfate/Dermatan Sulfate-Protein Interactions and Their Biological Functions in Human Diseases: Implications and Analytical Tools

2021 ◽  
Vol 9 ◽  
Author(s):  
Bin Zhang ◽  
Lianli Chi
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Protein Interactions ◽  
Dermatan Sulfate ◽  
Interaction Analysis ◽  
Structural Complexity ◽  
Protein Characterization ◽  
Biological Functions ◽  
Gag Protein ◽  
Core Proteins

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.

Oversulfated Chondroitin Sulfate Is Not the Sole Contaminant in Recalled Heparin Preparations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1070-1070
Author(s):  
Jawed Fareed ◽  
Eduardo Ramacciotti ◽  
Debra Hoppensteadt ◽  
Nasir Sadeghi ◽  
Arif Hussain ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Adverse Reactions ◽  
Dermatan Sulfate ◽  
Conflicts Of Interest ◽  
Serotonin Release ◽  
Contact System ◽  
Clinical Effects ◽  
Thrombin Time ◽  
Vasoactive Mediators

Abstract Abstract 1070 Poster Board I-92 Several reports have suggested that the contaminated heparin recalled by the regulatory bodies including the FDA and European community contained varying amounts of oversulafted chondroitin sulfate (OSCS). The reported adverse reactions and death were solely attributed to the presence of OSCS including the activation of the contact system and the generation of vasoactive mediators such as the bradykinins. The pathophysiologic nature of the adverse reactions were complex and multifactorial and not all of the adverse reactions can be attributed to an activation of the contact system by OSCS. To further explore the nature of the contaminants, several batches of contaminated recalled heparin from various sources were analyzed utilizing chemical and biologic methods. Such additional contaminants as high molecular weight dermatan sulfate (HDS), oversulfated heparan sulfate (OSHS), oversulfated dermatan sulfate (OSDS), oversulfated heparin sulfate (OSH) and other various forms of glycosaminoglycans were found in the contaminated heparin products. OSCS, HDS, OSDS and OSHS produced activation of prekallikrein to kallikrein in whole blood and plasma systems at variable rates as measured by monitoring the generation of kallkrein. All of the agents produced an activation of the complement system which was not proportional to the generation of kallikrein system. All of the contaminants were capable of forming complexes with PF4 and all produced 14C serotonin release in the HIT screening analysis. Variable anticoagulant responses occurred with each agent and were mediated via heparin cofactor II. Supplementation of various oversulfated agents showed that OSCS, OSDS and OSH produced comparable anticoagulant effects. Interestingly in the heptest, none of the oversulfated contaminants with the exception of heparin produced any anticoagulant effect. In the thrombin time assasy, OSH produced the strongest anticoagulant effects whereas OSDS and OSCS produced relatively weaker effects, while OSHS did not produce any effects. In the amidolytic anti-Xa assay, only OHS produced an inhibition of this enzyme, whereas, all of the other agents had no effects. In the anti-IIa assay all agents produced variable inhibitory effects. OSH produced the strongest inhibition with an IC50 of 4 ug/ml. OSCS inhibited this enzyme with an IC50 of 7.2 ug/ml and OSDS showed an IC50 of 11 ug/ml. The IC50 of OSHS was > 20 ug/ml. All agents showed a relatively weak affinity for antithrombin (AT). All agents were resistant to the actions heparinase-1. Both OSCS and OSDS produced an inhibition of heparinase. These results clearly suggest that heparin contaminants represent a heterogenous group of oversulfated GAGs which may mediate multiple pathophysiologic responses. The complex and diversed spectrum of the pathologic events in patients exposed to these contaminants need additional investigations to fully understand their adverse clinical effects in vivo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel Insight Into Glycosaminoglycan Biosynthesis Based on Gene Expression Profiles

2021 ◽  
Vol 9 ◽  
Author(s):  
Yi-Fan Huang ◽  
Shuji Mizumoto ◽  
Morihisa Fujita
Keyword(s):  
Gene Expression ◽  
Chondroitin Sulfate ◽  
Dermatan Sulfate ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Sulfate Proteoglycan ◽  
Expression Levels ◽  
Core Proteins ◽  
Dermatan Sulfate Proteoglycan ◽  
Insight Into

Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate, except for hyaluronan that is a free polysaccharide, are covalently attached to core proteins to form proteoglycans. More than 50 gene products are involved in the biosynthesis of GAGs. We recently developed a comprehensive glycosylation mapping tool, GlycoMaple, for visualization and estimation of glycan structures based on gene expression profiles. Using this tool, the expression levels of GAG biosynthetic genes were analyzed in various human tissues as well as tumor tissues. In brain and pancreatic tumors, the pathways for biosynthesis of chondroitin and dermatan sulfate were predicted to be upregulated. In breast cancerous tissues, the pathways for biosynthesis of chondroitin and dermatan sulfate were predicted to be up- and down-regulated, respectively, which are consistent with biochemical findings published in the literature. In addition, the expression levels of the chondroitin sulfate-proteoglycan versican and the dermatan sulfate-proteoglycan decorin were up- and down-regulated, respectively. These findings may provide new insight into GAG profiles in various human diseases including cancerous tumors as well as neurodegenerative disease using GlycoMaple analysis.

Contribution of chondroitin-dermatan sulfate-containing proteoglycans to the function of rat mesenteric arteries

1997 ◽  
Vol 273 (2) ◽  
pp. H952-H960 ◽  
Author(s):  
R. E. Gandley ◽  
M. K. McLaughlin ◽  
T. J. Koob ◽  
S. A. Little ◽  
L. J. McGuffee
Keyword(s):  
Arterial Wall ◽  
Dermatan Sulfate ◽  
Applied Pressure ◽  
Stress Transfer ◽  
Collagen Fibrils ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Functional Behavior ◽  
Core Proteins ◽  
Wall Stiffness

Proteoglycans are an important nonfibrous matrix component of the arterial wall. Direct evidence for their role in resistance-sized arteries is lacking, although they likely have an important role in coordinating and regulating vessel behavior, presumably via interactions of their glycosaminoglycan chains or core proteins with other matrix molecules and/or the smooth muscle cell surface. The purpose of this study was to determine whether the removal of specific glycosaminoglycan chains from proteoglycans in resistance-sized mesenteric arteries would change the mechanical properties of the arterial wall, thereby affecting their functional behavior. The major finding of the study was that 65% removal of chondroitin-dermatan sulfate-containing glycosaminoglycans from the arterial wall increased vascular wall stiffness and altered the myogenic behavior of the artery. The significant alterations in myogenic behavior associated with changes in passive mechanics following partial glycosaminoglycan chain removal support our hypothesis that chondroitin-dermatan sulfate-containing proteoglycans contribute significantly to the functional behavior of resistance arteries. We speculate that these alterations are the result of changes in stress transfer between collagen fibrils and/or stress transfer between cells and collagen fibrils under applied pressure.

Polyoxometalates in Biomedicine: Update and Overview

2020 ◽  
Vol 27 (3) ◽  
pp. 362-379 ◽  
Author(s):  
Mirjana B. Čolović ◽  
Milan Lacković ◽  
Jovana Lalatović ◽  
Ali S. Mougharbel ◽  
Ulrich Kortz ◽  
...  
Keyword(s):  
Biological Activities ◽  
Transition Metal Ions ◽  
Fine Tuning ◽  
Comprehensive Overview ◽  
Early Transition Metal ◽  
Biological Targets ◽  
Wide Range ◽  
Treatment Of Diabetes

Background: Polyoxometalates (POMs) are negatively charged metal-oxo clusters of early transition metal ions in high oxidation states (e.g., WVI, MoVI, VV). POMs are of interest in the fields of catalysis, electronics, magnetic materials and nanotechnology. Moreover, POMs were shown to exhibit biological activities in vitro and in vivo, such as antitumor, antimicrobial, and antidiabetic. Methods: The literature search for this peer-reviewed article was performed using PubMed and Scopus databases with the help of appropriate keywords. Results: This review gives a comprehensive overview of recent studies regarding biological activities of polyoxometalates, and their biomedical applications as promising anti-viral, anti-bacterial, anti-tumor, and anti-diabetic agents. Additionally, their putative mechanisms of action and molecular targets are particularly considered. Conclusion: Although a wide range of biological activities of Polyoxometalates (POMs) has been reported, they are to the best of our knowledge not close to a clinical trial or a final application in the treatment of diabetes or infectious and malignant diseases. Accordingly, further studies should be directed towards determining the mechanism of POM biological actions, which would enable fine-tuning at the molecular level, and consequently efficient action towards biological targets and as low toxicity as possible. Furthermore, biomedical studies should be performed on solutionstable POMs employing physiological conditions and concentrations.

scholarly journals Membrane-associated chondroitin sulfate proteoglycans of human lung fibroblasts.

1989 ◽  
Vol 108 (3) ◽  
pp. 1165-1173 ◽  
Author(s):  
G David ◽  
V Lories ◽  
A Heremans ◽  
B Van der Schueren ◽  
J J Cassiman ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Human Lung ◽  
Core Protein ◽  
Human Fibroblasts ◽  
Chondroitin Sulfate Proteoglycans ◽  
Lung Fibroblasts ◽  
Hydrophobic Membrane ◽  
Human Lung Fibroblasts ◽  
Core Proteins

Cultured human fetal lung fibroblasts produce some chondroitin sulfate proteoglycans that are extracted as an aggregate in chaotropic buffers containing 4 M guanidinium chloride. The aggregated proteoglycans are excluded from Sepharose CL4B and 2B, but become included, eluting with a Kav value of 0.53 from Sepharose CL4B, when Triton X-100 is included in the buffer. Conversely, some of the detergent-extractable chondroitin sulfate proteoglycans can be incorporated into liposomes, suggesting the existence of a hydrophobic membrane-intercalated chondroitin sulfate proteoglycan fraction. Purified preparations of hydrophobic chondroitin sulfate proteoglycans contain two major core protein forms of 90 and 52 kD. A monoclonal antibody (F58-7D8) obtained from the fusion of myeloma cells with spleen cells of BALB/c mice that were immunized with hydrophobic proteoglycans recognized the 90- but not the 52-kD core protein. The epitope that is recognized by the antibody is exposed at the surface of cultured human lung fibroblasts and at the surface of several stromal cells in vivo, but also at the surface of Kupffer cells and of epidermal cells. The core proteins of these small membrane-associated chondroitin sulfate proteoglycans are probably distinct from those previously identified in human fibroblasts by biochemical, immunological, and molecular biological approaches.

scholarly journals Cartilage Oligomeric Matrix Protein-Deficient Mice Have Normal Skeletal Development

2002 ◽  
Vol 22 (12) ◽  
pp. 4366-4371 ◽  
Author(s):  
Liz Svensson ◽  
Attila Aszódi ◽  
Dick Heinegård ◽  
Ernst B. Hunziker ◽  
Finn P. Reinholt ◽  
...  
Keyword(s):  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Skeletal Development ◽  
Clinical Signs ◽  
Immunohistochemical Analysis ◽  
Epiphyseal Dysplasia ◽  
Comp Gene ◽  
Deficient Mice

ABSTRACT Cartilage oligomeric matrix protein (COMP) belongs to the thrombospondin family and is a homopentamer primarily expressed in cartilage. Mutations in the COMP gene result in the autosomal dominant chondrodysplasias pseudoachondroplasia (PSACH) and some types of multiple epiphyseal dysplasia (MED), which are characterized by mild to severe short-limb dwarfism and early-onset osteoarthritis. We have generated COMP-null mice to study the role of COMP in vivo. These mice show no anatomical, histological, or ultrastructural abnormalities and show none of the clinical signs of PSACH or MED. Northern blot analysis and immunohistochemical analysis of cartilage indicate that the lack of COMP is not compensated for by any other member of the thrombospondin family. The results also show that the phenotype in PSACH/MED cartilage disorders is not caused by the reduced amount of COMP.

Systematic investigation of the skin in Chst14−/− mice: A model for skin fragility in musculocontractural Ehlers–Danlos syndrome caused by CHST14 variants (mcEDS-CHST14)

Glycobiology ◽  
2020 ◽  
Author(s):  
Takuya Hirose ◽  
Shuji Mizumoto ◽  
Ayana Hashimoto ◽  
Yuki Takahashi ◽  
Takahiro Yoshizawa ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Anion Exchange ◽  
Dermatan Sulfate ◽  
Systematic Investigation ◽  
Exchange Chromatography ◽  
Collagen Fibrils ◽  
Loss Of Function ◽  
Ehlers Danlos Syndrome ◽  
Skin Fragility ◽  
Danlos Syndrome

Abstract Loss-of-function variants in CHST14 cause a dermatan 4-O-sulfotransferase deficiency named musculocontractural Ehlers–Danlos syndrome-CHST14 (mcEDS-CHST14), resulting in complete depletion of the dermatan sulfate moiety of decorin glycosaminoglycan (GAG) chains, which is replaced by chondroitin sulfate. Recently, we uncovered structural alteration of GAG chains in the skin of patients with mcEDS-CHST14. Here, we conducted the first systematic investigation of Chst14 gene-deleted homozygote (Chst14−/−) mice. We used skin samples of wild-type (Chst14+/+) and Chst14−/− mice. Mechanical fragility of the skin was measured with a tensile test. Pathology was observed using light microscopy, decorin immunohistochemistry and electron microscopy (EM) including cupromeronic blue (CB) staining. Quantification of chondroitin sulfate and dermatan sulfate was performed using enzymatic digestion followed by anion-exchange HPLC. In Chst14−/− mice, skin tensile strength was significantly decreased compared with that in Chst14+/+ mice. EM showed that collagen fibrils were oriented in various directions to form disorganized collagen fibers in the reticular layer. Through EM-based CB staining, rod-shaped linear GAG chains were found to be attached at one end to collagen fibrils and protruded outside of the fibrils, in contrast to them being round and wrapping the collagen fibrils in Chst14+/+ mice. A very low level of dermatan sulfate disaccharides was detected in the skin of Chst14−/− mice by anion-exchange chromatography. Chst14−/− mice, exhibiting similar abnormalities in the GAG structure of decorin and collagen networks in the skin, could be a reasonable model for skin fragility of patients with mcEDS-CHST14, shedding light on the role of dermatan sulfate in maintaining skin strength.

scholarly journals Identification of keratan sulfate disaccharide at C-3 position of glucuronate of chondroitin sulfate from Mactra chinensis

2016 ◽  
Vol 473 (22) ◽  
pp. 4145-4158 ◽  
Author(s):  
Kyohei Higashi ◽  
Keita Takeda ◽  
Ann Mukuno ◽  
Yusuke Okamoto ◽  
Sayaka Masuko ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Chondroitin Sulfate ◽  
Hippocampal Neurons ◽  
Uronic Acid ◽  
Dermatan Sulfate ◽  
Biological Activities ◽  
Keratan Sulfate ◽  
Structural Variations ◽  
Low Concentrations ◽  
Mactra Chinensis

Glycosaminoglycans (GAGs), including chondroitin sulfate (CS), dermatan sulfate, heparin, heparan sulfate and keratan sulfate (KS) are linear sulfated repeating disaccharide sequences containing hexosamine and uronic acid [or galactose (Gal) in the case of KS]. Among the GAGs, CS shows structural variations, such as sulfation patterns and fucosylation, which are responsible for their physiological functions through CS interaction with CS-binding proteins. Here, we solved the structure of KS-branched CS-E derived from a clam, Mactra chinensis. KS disaccharide [d-GlcNAc6S-(1→3)-β-d-Gal-(1→] was attached to the C-3 position of GlcA, and consecutive KS-branched disaccharide sequences were found in a CS chain. KS-branched polysaccharides clearly exhibited resistance to degradation by chondroitinase ABC or ACII (at low concentrations) compared with typical CS structures. Furthermore, KS-branched polysaccharides stimulated neurite outgrowth of hippocampal neurons. These results strongly suggest that M. chinensis is a rich source of KS-branched CS, and it has important biological activities.

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