Wnt signalling in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a symmetrical polyarticular disease of unknown aetiology that affects primarily the diarthrodial joints. Characteristic features of RA pathogenesis are synovial hyperplasia and inflammation accompanied by cartilage loss and joint destruction. Synovial hyperplasia and inflammation are a consequence of an increase in the macrophage-like and fibroblast-like synoviocytes of the synovial intimal lining associated with infiltration of leucocytes into the subintimal space. Although therapeutic interventions are available, the disease persists despite therapy in a significant fraction of patients. Several lines of evidence have substantiated a crucial role of activated fibroblast-like synoviocytes (FLS) during RA pathogenesis. The hyperplastic FLS population potentially promotes leucocyte infiltration and retention. The rheumatoid synovium eventually transforms into a pannus that destroys articular cartilage and bone. There are no approved drugs that are known to target the FLS in RA, and the underlying mechanisms driving FLS activation remain unresolved. In this review, the importance of Wnt-frizzled (Fz)-mediated signalling in the autonomous activation of FLS is discussed. Anti-Wnt/anti-Fz antibodies, Fz receptor antagonists or small-molecule inhibitors of Wnt-Fz signalling might be useful for therapeutic interventions in refractory RA.
Sen
M
M
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA. msen@ucsd.edu
D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology; D051157:Frizzled Receptors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008957:Models, Genetic; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013583:Synovial Membrane / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D051153:Wnt Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin