STRUCTURAL FEATURES IN HEPARIN WHICH MODULATE SPECIFIC BIOLOGICAL-ACTIVITIES MEDIATED BY BASIC FIBROBLAST GROWTH-FACTOR

The biological activity of basic fibroblast growth factor (bFGF) is in fluenced greatly by direct binding to heparin and heparan sulphate (HS ). Heparin-derived oligosaccharides have been utilized to determine th e structural requirements present in the polymer that account for bind ing to bFGF. We had previously demonstrated that fragments > 6 mer can inhibit the interaction between cell surface heparan sulphate proteog lycan (HSPG) and bFGF, and bFGF-induced proliferation of adrenocortica l endothelial (ACE) cells. In contrast, oligosaccharides > 10 mer can enhance the binding of bFGF to its high-affinity receptor or support b FGF-induced mitogenesis in ACE cells (Ishihara et al., J. Biol. Chem., 268, 4675-4683, 1993). We have extended these studies to size- and st ructure-defined oligosaccharides from heparin, 2-0-desulphated (2-O-DS -) heparin, 6-0-desulphated (6-O-DS-) heparin, carboxy-reduced (CR-) h eparin and carboxy-amidomethylsulphonated (AMS-) heparin. Oligosacchar ides from these polymers were fractionated on a bFGF-affinity column a nd were assessed as inhibitors or enhancers of specific bFGF-derived b iological activities. The results of these studies indicate that both 2-0-sulphate and the negative charge of the carboxy group [L-iduronic acid (IdoA) residues] are required for specific interactions of hepari n-derived oligosaccharides with bFGF and for modulation of bFGF mitoge nic activity. In addition, the charge of the carboxy groups in uronic acids can be replaced by other functional groups with a negative charg e, such as the amidomethyl sulphonate moiety described here.