A Question of Transformation: The Synovial Fibroblast in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease with an unknown etiology. Both genetic and environmental factors contribute to disease susceptibility and the prevalence of RA is greater in women than in men. RA is characterized by initial vasculitis of the joint, followed by edema, infiltration of immune and inflammatory cells into the synovium, hyperplasia of the synovial lining, formation of lymph follicles, and development of the pannus. There is progressive cartilage destruction and finally erosion of the underlying bone. Current evidence suggests that fibroblast-like synoviocytes are one of the principle cells involved in pannus formation and cartilage degradation. Fibroblast-like synoviocytes in the rheumatoid synovium have characteristics similar to transformed cells and have been shown to proliferate in an anchorage-independent manner, lack contact inhibition, and express oncogenes and cell cycle proteins indicative of transformation. In vivo models have demonstrated that fibroblast-like synoviocytes can autonomously mediate cartilage destruction. In the article by Seemayer and colleagues in this issue of The American Journal of Pathology a direct comparison is made between SV40-transformed rheumatoid fibroblast-like synoviocytes and untransformed cells. 1 These experiments challenge the paradigm that rheumatoid synoviocytes are characterized by both aggressive growth and invasiveness. Of interest, the results demonstrate that fibroblast-like synoviocytes, capable of forming the pannus and invading cartilage, have an activated phenotype and secrete high levels of matrix-degrading enzymes, but have a limited capacity to proliferate. Conversely, SV40-transformed cells rapidly proliferate, secrete lower levels of matrix-degrading enzymes, display different levels of adhesion molecules, and demonstrate limited cartilage invasion. Thus these studies reveal an important dissociation between synoviocyte proliferation and invasiveness. This article reviews the tumor-like characteristics of fibroblast-like synoviocytes and discusses the contribution of synoviocytes to the pathogenesis of RA.