Wibulswas, A; (1999) Functional implications of CD44 splice variant expression in rheumatoid arthritis. Doctoral thesis , University of London.

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Abstract

Fibroblast-like synoviocytes (FLSs) are resident within the synovial membrane. In rheumatoid arthritis (RA), these cells dramatically increase in number and demonstrate a highly aggressive phenotype, characterised by the destruction of bone and cartilage and the release of a variety of cytokines. FLSs from RA patients have been demonstrated in this thesis to constitutively express alternatively spliced CD44 isoforms at the cell surface level, both in situ and in vitro. These cells show a greater intensity of staining for variant CD44 isoforms containing v3, v6 and v7/8, as compared to those from normal and osteoarthritic patients. This suggests that the expression of CD44 splice variants is closely linked to the inflammatory state of the diseased synovium and may be involved in the pathogenesis of RA. Several cell-based assays have been used to determine whether CD44 splice variants mediate any of the above characteristics. FLSs expressing variant isoforms containing v7/8 exhibit faster proliferation than non-expressing cells. Moreover, treatment with anti-CD44v7/8 monoclonal antibodies (mAbs) inhibits this proliferative advantage. On the other hand, CD44H and variants containing v3 or v6 have no effect on the proliferation of the cells. CD44 isoforms incorporating v3 or v6 are involved in cellular invasion as observed from in vitro invasion assays. MAbs against CD44v3 or CD44v6 inhibit invasion of extracellular matrix by FLSs while the anti-CD44v7/8 mAb does not. CD44 isoforms carrying v7/8 also appear to influence IL-6 release of the cultured FLSs as examined by enzyme-linked immunosorbent assays. These results indicate functional implications of particular CD44 splice variants that might allow pharmacological intervention using variant-specific antibodies.

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