A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor

Abstract

Synovial fluid cells from joints of rheumatoid arthritis (RA) patients express a novel variant of CD44 (designated CD44vRA), encoding an extra trinucleotide (CAG) transcribed from intronic sequences flanking a variant exon. The CD44vRA mutant was detected in 23 out of 30 RA patients. CD44-negative Namalwa cells transfected with CD44vRA cDNA or with CD44v3-v10 (CD44vRA wild type) cDNA bound FGF-2 to an equal extent via their associated heparan sulfate chains. However, Namalwa cells, immobilizing FGF-2 via their cell surface CD44vRA, bound substantially more soluble FGF receptor-1 (FGFR-1) than did Namalwa cells immobilizing the same amount of FGF-2 via their cell surface CD44v3-v10. The former cells stimulated the proliferation of BaF-32 cells, bearing FGFR-1, more efficiently than did the latter cells. Finally, isolated primary synovial fluid cells from RA patients expressing CD44vRA bound more soluble FGFR-1 to their cell surface–associated FGF-2 than did corresponding synovial cells expressing CD44v3-v10 or synovial cells from osteoarthritis patients. The binding of soluble FGFR-1 to RA synovial cells could be specifically reduced by their preincubation with Ab’s against the v3 exon product of CD44. Hence, FGF-2 attached to the heparan sulfate moiety expressed by the novel CD44 variant of RA synovium cells exhibits an augmented ability to stimulate FGFR-1–mediated activities. A similar mechanism may foster the destructive inflammatory cascade not only in RA, but also in other autoimmune diseases

Expression of extra trinucleotide in CD44 variant of rheumatoid arthritis patients allows generation of disease-specific monoclonal antibody

“…We previously showed that the CD44v3ev10 transcript of synovial fluid cells from the joints of RA patients (designated CD44vRA) contains an extra trinucleotide, CAG, which is not included in the corresponding wild type molecule, CD44v3e v10, predominantly expressed on primary keratinocytes [12]. We now describe the generation of mAbs exclusively recognizing CD44vRA and inducing apoptosis in synovial fluid cells from RA patients, but not in their PBLs.…”

“…Does expression of cell surface CD44vRA entail a functional meaning with physiological or pathological consequences? Namalwa cells and RA synovial fluid cells expressing CD44vRA and immobilizing FGF-2 activate FGF-receptor bearing cells more intensively than corresponding cells expressing the wild type CD44v3ev10 [12]. As activation of the FGF-receptor on fibroblasts and endothelial cells in inflammatory joints of RA patients is an important factor in the pathology of the disease [20e22], it is conceivable that CD44vRA expression contributes to the RA inflammatory process.…”

“…[12]) were isolated following joint aspiration. Their total RNA was reversed transcribed and subjected to PCR, using primers representing the constant coding regions of CD44 (hs 5 0 and hs 3 0 in Fig.…”

“…1A), skipping the entire variable region, generates the most ubiquitous isoform-standard CD44 (CD44s), predominantly expressed on hematopoietic cells [3]. Modifications in the alternative splicing regulation, either genetically inherited, or induced, for example, in the stressed pathological site, may further enrich the molecular diversity of CD44 by giving rise to CD44 variants (CD44v) with extra sequences illegitimately transcribed from the end of an intron adjacent to junction sites of the alternative splicing [12]. Such a mechanism may generate exclusive CD44 variants expressed on cells engaged in pathological activities, i.e., disease-specific CD44 molecules.…”

Interaction of CD44 and hyaluronic acid enhances biliary epithelial proliferation in cholestatic livers

“…Cell surface CD44 can be present as either the standard isoform or as variant isoforms in a cell-specific manner (2,32). The structural diversity of CD44 isoforms correlates with a diverse array of overlapping yet distinct functions in cell adhesion, migration, and proliferation (10,18,23). Alternations in CD44 expression have been documented in tissue inflammation, wound healing, and tumor metastasis (16) (5,8,37,39).…”