Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts

Abstract

For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis. During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts (RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential is underway.

Figure 1

Network of interactions of RASFs with cells and matrix. RASFs are sensitive to stimulation and modulation by numerous growth factors, cytokines and chemokines, as well as by direct interaction with immunologically active cells and matrix components within the rheumatoid synovium. DMARDs such as methotrexate and leflunomide can inhibit the activity of RASFs to produce proinflammatory and matrix-degrading enzymes by interfering with their intracellular metabolic pathways. Modified from Müller-Ladner [80]. AP, activator protein; DMARD, disease-modifying antirheumatic drug; ERK, extracellular signal-regulated kinse; JNK, c-jun amino-terminal kinase; MAP kinase, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; RASF, rheumatoid arthritis synovial fibroblast; RNAi, RNA interference; TLR, Toll-like receptor.