Heparan sulphate (HS)¹ is a member of the glycosaminoglycan family of sugars and is present in almost all metazoan organisms. HS possesses a great deal of structural diversity that can be altered spatially and temporally in cells and tissues. HS has many conserved functions throughout biology, one of which is the regulation of growth factor (GF) activity. The variety of HS present on cell surfaces and in the matrix in tissues could be one way that organisms regulate GF activity during development and other processes such as wound healing. Here we review some of the evidence for HS egulation of GF activity during development and in disease processes, describe how HS can carry out these activities and how research into HS structure and function has recently progressed.

View full abstract

Perlecan has multiple functions in cell growth and differentiation and tissue homeostasis. Recent studies with mutant mice and human genetic disorders have shed light into the in vivo functions of perlecan. Complete deficiency of perlecan results in embryonic and perinatal lethality with severe defects in cartilage, cephalic development and cardiovascular systems. In adult tissues, perlecan is essential for high density clustering of acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) and partially functional mutations of perlecan result in myotonia and milder chondrodysplasia. Deletion of a short coding sequence including the HS attachment sites of the N-terminus of perlecan in mice revealed that the HS chains are not essential for development but play a role in supporting the integrity of the lens capsule, in promoting angiogenesis and tumor growth, and filtration in the kidney. In vitro studies indicate that many extracellular molecules and cell surface receptors interact with the HS chains and core protein of perlecan. Perlecan may work as a modulator for growth factor signaling and a ligand reservoir.

View full abstract

Heparan sulfate proteoglycans (HSPGs)¹ are important regulators of cell adhesion and cell signaling. The specific functions of these molecules are determined by both the core protein and the structure of the attached heparan sulfate chains. There is mounting evidence that HSPGs are remodeled by enzymes present on the surface of tumor cells or within the extracellular compartment. This remodeling within the tumor microenvironment leads to structural and functional alterations in HSPGs that regulate the behavior of tumor cells, including their growth and metastatic properties. This minireview focuses on the effects of sheddases, endosulfatases and heparanase on syndecan-1 function and how this controls the behavior of myeloma tumors.

View full abstract

The epithelium plays a vital role in regulating tissue injury and inflammation because it frequently encounters and detects harmful agents that can initiate the inflammatory host response. The epithelium also elaborates cytokines, antimicrobial factors, proteinases, and other key inflammatory mediators, and regulates the recruitment of inflammatory cells to sites of tissue injury. Syndecan-1 is a major cell surface heparan sulfate proteoglycan of the epithelium that can bind and regulate many inflammatory factors through its heparan sulfate chains. Syndecan-1 expression and its secretion into the extracellular milieu by ectodomain shedding are regulated by various inflammatory mediators and pathological conditions. Recent data indicate that syndecan-1 protects the host from various non-infectious inflammatory disorders by coordinating epithelial cell proliferation and migration, neutralizing chemokines, attenuating exaggerated T lymphocyte homing, and by confining neutrophil migration to specific sites of tissue injury. However, several pathogens have devised schemes to take advantage of syndecan-1 to promote their pathogenesis. These findings indicate that syndecan-1 is a key molecule that modulates host responses to tissue injury in normal repair and in the pathogenesis of inflammatory diseases.

View full abstract

Glycans have the potential to carry more variation than either proteins or nucleic acids. Terminal glycan variation exists both between as well as within species as distant as bacteria and humans. The reasons for this extensive variation are still elusive. This includes the most well known example of polymorphic terminal glycosylation, the ABO histo-blood group family of antigens. A number of associations with infectious diseases have been described, which have become focused on differential adherence by different pathogens to ABO antigens at mucosal surfaces. Histo-blood group antigens can, however, also be carried by virus, as determined by the host cell. When the virus enters a new host, it is likely that it encounters natural antibodies with specificity for the histo-blood group antigens that it carries. We believe that this leads, not only to increased direct neutralisation of the virus, but also to an increased specific immune response to the virus. When taking both of these interactions with pathogens into account in a modelling study, we have shown that the two selective forces together can explain the ABO type frequencies typically seen in human populations and could thus explain how and why these types of terminal glycan polymorphisms have evolved.

View full abstract