Biosynthesis of Dermatan Sulphate. Enzymatic mechanism and role of cytokines

Abstract: Dermatan sulphate is a prominent feature of several different proteoglycans and occurs in almost every tissue of the body. It is an unbranched polymer containing the repeating disaccharide unit of N-acetylgalactosamine and D-glucuronic acid or L-iduronic acid. The polymer can be highly sulphated resulting in an unusual and largely unknown diversity in the chain. The unique step in dermatan sulphate synthesis is the conversion of glucuronic acid into iduronic acid, performed by the action of the dermatan sulphate C5-epimerase. This is followed by a subsequent C4-sulphation of the N-acetylgalactosamine unit by a 4-O-sulphotransferase. C5-epimerase and 4-O-sulphotransferase were quantitated in tissues producing dermatan/chondroitin sulphate of different structures. Varying amounts of enzyme activity corresponded to different amounts of iduronic acid and, in tissue devoid of iduronic acid no epimerase could be demonstrated. In contrast, adequate amounts of 4-sulphotransferase were detected indicating a regulating role for the C5-epimerase in dermatan sulphate synthesis. A possible mechanism to generate the varation in content and organisation of iduronic acid in dermatan sulphate is the influence of various cytokine expressions. To investigate this, fibroblasts were either treated with epidermal growth factor, transforming growth factor-ß and platelet derived growth factor-BB singly or in combination. This resulted in a profound change in proteoglycan production, where biglycan in particular was increased after treatment with a combination of cytokines. Furthermore, treatment with cytokines decreased the C5-epimerase activity, which resulted in a change in dermatan sulphate structure with an increased number of glucuronic acid residues. The 4-O-sulphotransferase and glycosaminoglycan chain length was unaffected. The co-polymeric structure of dermatan sulphate is essential for the interaction with matrix components such as cytokines, proteases and cell surface receptors. An increased knowledge of the structure and how its synthesis is regulated would create a greater understanding of tissue remodelling in physiological, as well as pathophysiological conditions.