Pathogenesis of rheumatoid arthritis: the role of synoviocytes.

Considering the characteristics of RA synovial tissues such as marked proliferation and invasion to adjacent tissues, comparisons with transformed or neoplastic tissue are natural. RA synovial tissues or cells are not truly malignant, but they have many features of transformation, denoted as "partial transformation" in this article. These features include anchorage-independent growth, loss of contact inhibition, oncogene activation, monoclonal or oligoclonal expansion, detectable telomerase activity, and somatic gene mutations. Although it is not possible to conclude whether most of these cells are permanently changed in association with some genetic alterations or are passively changed by virtue of environmental factors (i.e., cytokine-mediated imprinting), the presence of p53 mutations in RA synovial tissues is especially persuasive. A number of transcription factors play a critical role in the activation, differentiation, and proliferation of RA synovial cells. In particular, the roles of AP-1, MAPKs, and NF-kappa B have been investigated carefully because of their ability to regulate numerous inflammation-related genes. These transcription factors also control expression and activation of matrix-degrading enzymes, including MMPs, aggrecanase, and cysteine proteases, which are the primary enzymes responsible for joint destruction. Elucidation of gene mutations and detailed signal transduction pathways that are specific to RA as well as mechanisms of action of matrix-degrading enzymes may lead to development of a novel therapy for RA. Careful mapping of cytokine networks a decade ago led to groundbreaking advances in therapy. Similarly, methodical evaluation and prioritization of intracellular targets might provide the basis for therapeutic interventions.