|Figure 1. The four families of cell-surface HSPGs. Glycosaminoglycan chains (GAG) are shown as broad lines (heparan sulfate) or narrow lines (chondroitin sulfate). The Syndecans are developmentally regulated integral-membrane proteoglycans encoded by separate genes;11 the Glypicans are cysteine-rich GPI-anchored proteoglycans; Betaglycan is the type III low-affinity receptor for transforming growth-factor beta (TGF-beta);1 and the CD44 HSPGs are forms generated by alternative RNA splicing12,13 leading to insertion of up to nine alternative exons (v2-v10).|
Cell-surface heparan sulfate proteoglycans (HSPGs) are an abundant and widely expressed group of macro molecules.1 Of major interest is the ability of these molecules to bind heparin-binding growth factors and chemokines (Table 1). Indeed, the productive binding of many, if not all, of these factors to their signal-transducing receptors is critically dependent on interactions with HSPGs.2 Heparin-binding factors and HSPGs, especially CD44 HSPGs, are attractive targets for new anti-inflammatory drugs.
The best characterized cell-surface HSPG molecules fall into four groups (Fig. 1), Syndecans, Glypicans, Betaglycan, and the CD44 family proteins. The majority of CD44 isoforms on most cells are not proteoglycans, but a distinct population of proteoglycans arises from alternative splicing leading to heparan sulfate attached via a Ser-Gly-Ser-Gly motif.3 These unusually complex adhesion molecules are involved in the homing of activated leukocytes to inflamed tissues.4,5
HSPGs on inflamed endothelial cells are believed to sequester chemokines and present them to their cognate receptors on patrolling leukocytes.6 Lymphocytes and monocytes synthesize heparin-binding growth factors and chemokines as part of their roles in inflammation, wound healing, and tissue remodeling. While no HSPG is expressed on normal, resting leukocytes, expression of CD44 HSPG isoforms is induced on human monocytes by IL-1 or LPS-induced cell activation.7
What is the function of monocyte CD44 HSPGs? One possibility is that CD44 HSPGs bind chemokines released from neighboring leukocytes or endothelial cells as part of monocyte chemotaxis. No interaction between CD44 HSPGs and the leukocyte chemokines MCP-1, RANTES, MIP-1 alpha, or MIP-1 beta has been observed in radioligand binding assays with either CD44-transfected cells or soluble CD44 HSPG immuno globulin fusion proteins.14 On the other hand, HSPG isolated from endothelial cells binds the alpha chemokine IP-10 with a Kd of 25 nM.8 Additionally, beta chemokines, including MIP-1 beta, have been directly visualized on vascular endothelial tissue sections by immunohistochemical staining.9
Another possibility is that monocyte CD44 HSPGs bind heparin-dependent growth factors, such as FGF-2 (FGF basic) or VEGF, that promote tissue growth and neovascularization. In common with Syndecan-1 and Syndecan-3, CD44 HSPGs also display heparin-inhibitable binding to FGF-2.10 The CD44-FGF-2 interaction has been measured not only by radioligand blotting of immunoglobulin fusion proteins expressed in COS-7 cells but also by quantitative radioligand binding assays with CD44-transfected tumor cell lines and activated monocytes. It appears to involve affinities in the range of 10-7M.14 Since monocytes are known to produce FGF-2 in response to inflammation, it may be that CD44 HSPGs display endogenously synthesized growth factor for presentation to neighboring target cells bearing the appropriate high-affinity receptors.
The situation is more complex than initially anticipated, since activated monocytes express a number of cell-surface HSPGs in addition to the CD44 isoforms.14 It will be intriguing to know the identity of these additional molecules, their ligand binding properties and their individual functions in the inflammatory process.