The Alterations and Roles of Glycosaminoglycans in Human Diseases

Abstract

Glycosaminoglycans (GAGs) are a heterogeneous family of linear polysaccharides which are composed of a repeating disaccharide unit. They are also linked to core proteins to form proteoglycans (PGs). GAGs/PGs are major components of the cell surface and the extracellular matrix (ECM), and they display critical roles in development, normal function, and damage response in the body. Some properties (such as expression quantity, molecular weight, and sulfation pattern) of GAGs may be altered under pathological conditions. Due to the close connection between these properties and the function of GAGs/PGs, the alterations are often associated with enormous changes in the physiological/pathological status of cells and organs. Therefore, these GAGs/PGs may serve as marker molecules of disease. This review aimed to investigate the structural alterations and roles of GAGs/PGs in a range of diseases, such as atherosclerosis, cancer, diabetes, neurodegenerative disease, and virus infection. It is hoped to provide a reference for disease diagnosis, monitoring, prognosis, and drug development.

Keywords: ECM remodeling; chondroitin sulfate; dermatan sulfate; glycosaminoglycan; heparan sulfate; human disease.

Figure 1

Distribution and structures (repeating disaccharide units) of GAGs in the extracellular matrix. CS/DS, HS, and KS are linked to core proteins, whereas HA is free. “” and “” indicate that the hydroxyl can be substituted by a sulfate group and acetyl, respectively. It is worth noting that the structural formula represents the maximum degree of sulfation for each GAG type. “” only represents the possibility of being substituted by a sulfate group. Such as CS, they can be classified as CS-A (GlcA-GalNAc4S), CS-C (GlcA-GalNAc6S), CS-D (GlcA2S-GalNAc6S), CS-E (GlcA4S-GalNAc6S), etc. (Used with permission of Royal Society of Chemistry from ref. [1]; permission conveyed through Copyright Clearance Center, Inc).

Figure 2

Schematic diagram of the ternary complex of FGF/HS/FGFR and the key sites for HS binding. (a) FGFR comprises extracellular Ig-like domains, intracellular tyrosine kinase domains, and transmembrane domain. Ig-like domains bind FGF with the assistance of HS to form ternary complex; (b) HS binding to FGF2 requires 2-O-S of IdoA and N-S of GlcN; HS binding to FGF1 and FGFR requires 2-O-S of IdoA and 6-O-S, N-S of GlcN; the N-S of the nonreducing terminal residue is also necessary for HS binding to FGF/FGFR. The increased expression of HS in most tumor cells enhances FGF/FGFR signal transduction, which is beneficial to tumor cell growth and angiogenesis. (The data of the HS sequence is cited from reference [96,97,98,99]).