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 . 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.