Expression and function of wingless and frizzled homologs in rheumatoid arthritis

Rheumatoid arthritis (RA) is accompanied by synovial inflammation, prolifer ation, and cartilage destruction. The reasons the activation of synovial fi broblasts often persists despite antiinflammatory therapy are not known. On e possibility is that the synovial membrane becomes gradually repopulated w ith immature mesenchymal and bone marrow cells with altered properties. To explore this hypothesis, we have investigated the expression in RA synovial tissues of various embryonic growth factors from the wingless (wnt) and fr izzled (fi) families, which have been implicated in cell-fate determination in both bone marrow progenitors and limb-bud mesenchyme, Reverse transcrip tase-PCR analysis revealed expression of five wnt(wnt1, 5a, 10b, 11, and 13 ) and three fi (fz2, 5, and 7) isoforms in RA synovial tissues. Osteoarthri tis synovial tissues expressed much less wnt5a and fz5, Northern blotting c onfirmed the overexpression of wnt5a and fz5 in RA synovial tissues, in com parison to a panel of normal adult tissues. Compared with normal synovial f ibroblasts, cultured RA fibroblastlike synoviocytes expressed higher levels of IL-6, IL-8, and IL-15. Transfection of normal fibroblasts with a wnt5a expression vector reproduced this pattern of cytokine expression and stimul ated IL-15 secretion. These results suggest that the unusual phenotypic pro perties of RA fibroblasts may be attributable partly to their replacement w ith primitive fibroblast-like synoviocytes with characteristics of immature bone marrow and mesenchymal cells. Clear delineation of the signaling path way(s) initiated by the wnt5a/fz5 ligand-receptor pair in the RA synovium m ay yield new targets for therapeutic intervention.