heparitin-sulfate and Disease

Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell-cell and cell-extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an "activator" of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate-heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.

Topics: Disease; Glucuronidase; Heparitin Sulfate; Humans

Heparan sulfate (HS) proteoglycans (PGs) are ubiquitously expressed on cell surfaces and in the extracellular matrix of most animal tissues, having essential functions in development and homeostasis, as well as playing various roles in disease processes. The functions of HSPGs are mainly dependent on interactions between the HS-side chains with a variety of proteins including cytokines, growth factors, and their receptors. In a given HS polysaccharide, negatively charged sulfate and carboxylate groups are arranged in various types of domains, generated through strictly regulated biosynthetic reactions and with enormous potential for structural variability. The mode of HS-protein interactions is assessed through binding experiments using saccharides of defined composition in vitro, signaling assays in cell models where HS structures are manipulated, and targeted disruption of genes for biosynthetic enzymes in animals (mouse, zebrafish, Drosophila, and Caenorhabditis elegans) followed by phenotype analysis. Whereas some protein ligands appear to require strictly defined HS structure, others bind to variable saccharide domains without apparent dependence on distinct saccharide sequence. These findings raise intriguing questions concerning the functional significance of regulation in HS biosynthesis and the potential for development of therapeutics targeting HS-protein interactions.

Topics: Animals; Disease; Disease Models, Animal; Heparitin Sulfate; Humans; Models, Molecular; Protein Binding; Proteins

Heparan sulfate (HS) proteoglycans at cell surfaces and in the extracellular matrix of most animal tissues are essential in development and homeostasis, and variously implicated in disease processes. Functions of HS polysaccharide chains depend on ionic interactions with a variety of proteins including growth factors and their receptors. Negatively charged sulfate and carboxylate groups are arranged in various types of domains, generated through strictly regulated biosynthetic reactions and with enormous potential for structural variability. The level of specificity of HS-protein interactions is assessed through binding experiments in vitro using saccharides of defined composition, signaling assays in cell culture, and targeted disruption of genes for biosynthetic enzymes followed by phenotype analysis. While some protein ligands appear to require strictly defined HS structure, others bind to variable saccharide domains without any apparent dependence on distinct saccharide sequence. These findings raise intriguing questions concerning the functional significance of regulation in HS biosynthesis.

Topics: Animals; Carbohydrate Sequence; Disease; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Models, Molecular; Molecular Sequence Data; Protein Conformation; Proteins; Structure-Activity Relationship

The glycosaminoglycan, heparan sulfate (HS) is composed of alternating units of hexuronic acid and glucosamine, that are variously sulfate-substituted at different positions. Proteoglycans carrying HS chains are ubiquitously expressed at cell surfaces and in the extracellular matrix. The structures of these chains are highly variable, yet under strict biosynthetic control. Due to their high negative charge, HS chains interact with a multitude of proteins, including growth factors/morphogens and their receptors, chemokines, and extracellular-matrix proteins. These interactions regulate key events in embryonic development and in homeostasis. HS-protein interactions vary with regard to specificity, and often seem to depend primarily on charge density rather than on strict carbohydrate sequence. The organization of sulfated domains along the HS chain appears to be of importance. HS-protein interactions are involved in a variety of pathophysiological processes, including inflammation, angiogenesis, and amyloid deposition. Drugs targeting such interactions may be useful in treatment of disease conditions as diverse as cancer, inflammatory bowel disease, and Alzheimer's disease. Potential drugs may mimick HS oligosaccharides, but could also be peptides blocking the protein-binding domains of HS chains. Drug generation requires a firm understanding of the pathophysiological role of a given HS-protein interaction, and of the aspect of specificity. Even inhibition of HS biosynthesis may be considered.

Topics: Antithrombin III; Binding Sites; Disease; Drug Delivery Systems; Drug Design; Drug Therapy; Heparitin Sulfate; Humans; Protein Binding; Proteins