CD44 in rheumatoid arthritis

Abstract

CD44 is a multistructural cell-surface glycoprotein that can theoretically generate close to 800 isoforms by differential alternative splicing. At present, several dozen isoforms are known. The polymorphic nature of CD44 might explain its multifunctionality and its ability to interact with many cell-surface and extracellular ligands, the principal one being hyaluronic acid (HA). Of the many CD44 functions, our review focuses on its involvement in cell-cell and cell-matrix interactions, as well as on its implication in the support of cell migration and the presentation of growth factors to their cognate receptors. Cells involved in pathological activities such as cancer cells and destructive inflammatory cells, and also normal cells engaged in physiological functions, use cell-surface CD44 for their localization and expansion at extravascular sites. This article reviews the evidence that the joint synovium of patients with rheumatoid arthritis (RA) contains considerable amounts of various CD44 isoforms as well as the HA ligand. The review also shows that anti-CD44 monoclonal antibody (mAb) directed against constant epitopes, shared by all CD44 isoforms, can markedly reduce the inflammatory activity of arthritis induced by collagen or proteoglycans in mice. Anti-CD44 mAb also interferes with the migration of RA synovial-like fibroblasts in vitro and is able to disturb the destructive interaction between RA synovial-like fibroblasts and the cartilaginous matrix. However, the transition from the experimental model to the patient's bedside is dependent on the ability to target the CD44 of cells engaged in RA pathology, while skipping the CD44 of normal cells.

Figure 1

Structure, function and exon organization of CD44. (A) Structure and functions of CD44 glycoprotein [1-4]. CD44 structure. The heavy and intermediate black tracks represent the conserved N-terminal region of the extracellular domain, the transmembrane region and the cytoplasmic tail. The heavy black track at the N terminus represents the link module. The thin black track represents the nonconserved membrane-proximal region. Filled circles, potential N-linked glycosylation sites; open circles, potential O-linked glycosylation sites; filled diamonds, sites for glycosaminoglycan (chondroitin sulfate [CS] or heparan sulfate [HS]) attachments (the HS of exon v3 is involved in the binding of growth factors); P, potential sites for phosphorylation. Insets: CD44 functions. Inset a, the basic cluster and the amino acids critical to HA binding. Inset b, binding sites for ezrin radixin moesin (ERM) and for ankyrin as well as two phosphorylation sites; the location of the sugars and the functional sites is for illustrative purposes only. (B) CD44 isoforms: exon map. Filled circles represent the constant-region exons; open circles represent exons that can be inserted by alternative splicing, resulting in the generation of the variable region. Note that exon v1 is not expressed in human CD44. LP, leader peptide-encoding exon; TM, transmembrane-encoding exon; CT, cytoplasmic tail-encoding exon. (C) Examples of alternatively spliced transcripts: 1, standard CD44, which lacks the entire variable region; 2, pMeta-1 (CD44v4–v7; exons v4, v5, v6 and v7 are inserted in tandem between exons 5 and 17 [residues 204 and 205]); 3, pMeta-2 (CD44v6,v7) (pMeta-1 and pMeta-2 are known as metastatic CD44 because their cDNA confers, upon transfection, metastatic potential on nonmetastatic rat tumor cells); 4, epithelial CD44 (CD44v8–v10); 5, keratinocyte CD44 (CD44v3–v10). This figure is reproduced from Wiley Encyclopedia of Molecular Medicine, CD44 entry by D Naor and S Nedvetzki, vol 5, pp 619–624 (2002), by permission of John Wiley and Sons, Inc.