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Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical and chronic polyarthritis. Fibroblast-like synoviocytes are mainly involved in joint inflammation and cartilage and bone destruction by inflammatory cytokines and matrix-degrading enzymes in RA. Approaches that induce various cellular growth alterations of synoviocytes are considered as potential strategies for treating RA. However, since synoviocytes play a critical role in RA, the mechanism and hyperplastic modulation of synoviocytes and their motility need to be addressed. In this review, we focus on the alteration of synoviocyte signalling and cell fate provided by signalling proteins, various antioxidant molecules, enzymes, compounds, clinical candidates, to understand the pathology of the synoviocytes, and finally to achieve developed therapeutic strategies of RA.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation of the synovial membrane ultimately leading to permanent damage in the affected joints. For this study, synovial fluids from 16 patients diagnosed with either RA or osteoarthritis (OA) were used to examine volume regulation and cooperative water channels, both of which are involved in the cytotoxic edema identified in RA-fibroblast-like synoviocytes (FLS). The osmolarity and inflammatory cytokine interleukin (IL)-6 of synovial fluids from RA patients were mildly enhanced compared to that from OA patients. RA-FLS demonstrated the enhanced property of regulatory volume increase in response to IL-6 and synovial fluids from RA patients. Although there was no difference in the protein expression of the volume-associated protein sodium–potassium–chloride cotransporter1 (NKCC1), its activity was increased by treatment with IL-6. Membrane localization of NKCC1 was also increased by IL-6 treatment. Additionally, both the protein and membrane expressions of aquaporin-1 were increased in RA-FLS by IL-6 stimulation. The IL-6-mediated enhanced osmotic sensitivity of RA-FLS likely involves NKCC1 and aquaporin-1, which mainly constitute the volume-associated ion transporter and water channel elements. These results suggest that RA-FLS provide enhanced electrolytes and concomitant water movement through NKCC1 and aquaporin-1, thereby inducing cellular swelling ultimately resulting in cytotoxic edema. Attenuation of cytotoxic edema and verification of its related mechanism will provide novel therapeutic approaches to RA treatment within the scope of cytotoxic edema.

The purpose of this study was to investigate the diagnostic utilities of anti-agalactosyl IgG antibody (CARF), anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) in rheumatoid arthritis (RA), non-RA rheumatic diseases, and chronic viral hepatitis. The authors determined serum levels of CARF and anti-CCP2 by ELISA and IgM-RF by a immunonephelometric method in 834 controls and in 397 patients with the following conditions: RA (100), non-RA rheumatic diseases [systemic lupus erythematosus (SLE) 30, primary Sjogren's syndrome 18, systemic sclerosis 30, inflammatory myositis 19], chronic viral hepatitis B and C (HBV 100, HCV 100). The sensitivities of CARF (83%) and anti-CCP (85%) were significantly higher than that of RF (75%, p = 0.01, respectively) in RA, and the specificity of anti-CCP (98%) was significantly higher than those of CARF (92%) and RF (90%, p < 0.001, respectively). A comparison of receiver operating characteristic (ROC) curves revealed that the diagnostic accuracies of CARF and anti-CCP were superior to that of RF (CARF vs. RF, p = 0.008, anti-CCP vs. RF, p = 0.017) in RA. CARF positivity was significantly higher than those of anti-CCP ( p = 0.007) and RF ( p = 0.008) in systemic sclerosis, and the positivity of CARF was significantly higher than that of anti-CCP in Sjogren's syndrome ( p = 0.016). Furthermore, CARF had significantly higher positivity than anti-CCP or RF in chronic viral hepatitis B and C. Finally, the titers of these three markers in RA were significantly higher than in non-RA rheumatic diseases and in chronic viral hepatitis B and C. Our results suggest that anti-CCP is the most useful serologic marker for the differentiation of RA and non-RA rheumatic diseases, and chronic viral hepatitis B and C. [ABSTRACT FROM AUTHOR]