Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that may affect many tissues and organs, but mainly targets the synovial membrane, cartilage and bone. RA affects about 1% of the world's population, is three times more frequent in women than in men, and is associated with significant disability and increased mortality. The articular manifestations of RA are mediated by extensive infiltration of inflammatory cells into the synovium and proliferation of synovial fibroblasts of the joint lining, leading to the formation of pannus tissue which invades and destroys the articular cartilage and bone.The crucial triggers for the onset of RA are still incompletely known, but genetic and environmental factors both appear to play roles. Several genetic loci (HLA-DR4 and related allotypes of MHC class II, PTPN22, PAD14, CTLA4, FcγR, and various cytokines) have been shown to have an association with the susceptibility and severity of RA. Environmental factors (pathogen, smoking) may also have an impact on the induction and progression of the disease.
The key features of RA are autoimmunity, chronic inflammation and destruction of the cartilage and bones.
Cartilage degradation is mediated by osteoclasts, chondrocytes and synovial fibroblasts when the inflamed synovium invades adjacent cartilage. Cytokines such as IL-1, IL-6, IL-17 and TNF induce a switch in the synthesis pattern of chondrocytes from an anabolic state to a catabolic state (PMID: 17525752). Chondrocytes stop synthesizing matrix molecules and start producing matrix-degrading enzymes, such as aggrecanases and matrix metalloproteinases (MMP), which cleave cartilage components such as proteoglycan and collagen fibers (PMIDs: 11178124,17525752,18771589). Matrix-degrading enzymes are also released by invading synovial fibroblasts (PMIDs: 15705634, 12428226,3143380,7531366,9537651,15585320,11167130).
Apart from cartilage damage, RA is characterized by erosion of the underlying bone. The receptor activator of nuclear factor-κB ligand (RANKL) seems to be a crucial mediator in this process. In healthy joints, bone deposition by osteoblasts is in balance with bone resorption by osteoclasts. Osteoblasts rely on WNT signaling for their maturation and their control of osteoclast maturation and activation via production of the osteoclast-promoting growth factors M-CSF (PMIDs: 15615495,18799853) and RANKL (PMID: 17572649), as well as the osteoclast-limiting factor and RANKL antagonist, osteoprotegerin (OPG) (PMID: 16150701). In RA, cells of the adaptive and innate immune systems contribute to bone destruction through production of cytokines. Pro-inflammatory cytokines are mainly produced by macrophages and synovial fibroblasts (e.g. IL-1, IL-6, TNF) and Th17 cells (IL-17). TNF upregulates DKK-1, which inhibits WNT signaling in osteoblasts, causing a decreased OPG expression and blocking bone formation. IL-17 leads also to OPG downregulation, whereas IL-17 and IL-1 promote RANKL upregulation, creating an imbalance between RANKL and OPG expression. RANKL binds to RANK receptors on osteoclast precursors triggering osteoclast maturation and activation. Activated osteoclasts erode bone and consequently are critically involved in rheumatoid arthritis pathology (PMID: 17525752).