Proteoglycan Involvement in Inflammatory Diseases. New Developments in GAG-Based Therapies

Proteoglycans (PG) are complex macromolecules which consist structurally of a core protein and associated glycosaminoglycan (GAG) chains. The different GAG chains of PG, heparan sulfate/heparin, dermatan/chondroitin sulfate, keratan sulfate are synthesized as polymers of repeating disaccharide units. The structures of GAG chains are highly diverse and confer to them a variety of structures and functions. Without covering PG complexity in structures and roles, the most usual classification for PG is based on their localization: being at the cell membrane or in the extracellular matrix, being intracellular or circulating in the blood. By virtue of the multiplicity of protein binding partners (e.g. growth factors, chemokines), PG have been shown to be involved in the regulation of a large number of pathophysiological processes. They are strongly implicated in the different stages of inflammation from the recruitment of inflammatory cells to the release of mediators of inflammation by infiltrating leukocytes and the turnover of extracellular matrix. The overarching theme of PG in inflammation is the regulation of the inflammatory microenvironment, which has to change continuously and dynamically during the progression of the inflammatory response. These changes include the modulation of the activity of GAG-binding cytokines, growth factors, proteases and protease inhibitors. The interactions of regulatory proteins with GAGs provide much of the focus for GAG-based therapeutic targets and the development of GAG mimetics could have in the near future, clinical applications as modulators of cytokine or enzyme functions in inflammatory diseases.