The role of resident synovial cells in destructive arthritis
Infiltration by inflammatory cells, thickening of the lining layer, and destructive invasion into cartilage and bone are pathognomic features of the synovium in rheumatoid arthritis (RA). However, the most common cell types at the sites of invasion are resident cells of the joint, in particular synovial fibroblasts. These cells differ from healthy synovial fibroblasts in their morphology, their expression of proto-oncogenes and antiapoptotic molecules, and in their lack of certain tumor suppressor genes. Through their production of proinflammatory cytokines and chemokines mediated by signaling via Toll-like receptors, they are not only effector cells but also active parts of the innate immune system attracting inflammatory immune cells to the synovium. Most importantly, by producing matrix-degrading molecules they contribute strongly to the destructive mechanisms operative in RA.
Available from: Ondřej Pecha
- "In RA, persistent synovial inflammation and invasive behaviour by activated synovial fibroblasts contribute to joint damage, leading to disability . The discovery of novel molecules has contributed to a better understanding of RA pathogenesis and may lead to the identification of biomarkers that would allow for the monitoring of disease activity and individualising prognosis in RA patients . "
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To evaluate circulating visfatin and its relationship with disease activity and serum lipids in patients with early, treatment-naïve rheumatoid arthritis (RA).
Serum visfatin was measured in 40 patients with early RA before and after three months of treatment and in 30 age- and sex-matched healthy individuals. Disease activity was assessed using the Disease Activity Score for 28 joints (DAS28) at baseline and at three and 12 months. Multivariate linear regression analysis was performed to evaluate whether improved disease activity is related to serum visfatin or a change in visfatin level.
Serum visfatin was significantly elevated in early RA patients compared to healthy controls (1.92±1.17 vs. 1.36±0.93 ng/ml; p = 0.034) and significantly decreased after three months of treatment (to 0.99±0.67 ng/ml; p<0.001). Circulating visfatin and a change in visfatin level correlated with disease activity and improved disease activity over time, respectively. A decrease in visfatin after three months predicted a DAS28 improvement after 12 months. In addition, decreased serum visfatin was not associated with an improved atherogenic index but was associated with an increase in total cholesterol level.
A short-term decrease in circulating visfatin may represent an independent predictor of long-term disease activity improvement in patients with early RA.
Available from: Ali Mobasheri
- "RA can lead to joint and cartilage damage, significant disability, and reduction in quality of life. RA is a multifactorial disease and classified as an autoimmune disorder, that primarily affects the small diarthrodial joints of the hands and feet and affects multiple joints throughout the body . Although the etiology of RA is not yet fully understood , it is believed to be caused by a combination of environmental (microbial and viral triggers), immunomodulatory, genetic predisposition factors and a number of inflammatory pathways in response to endogenous and/or exogenous antigens . "
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ABSTRACT: We have previously reported that bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA) in an in vitro model that simulates the potential effects of residing in damp buildings. Since numerous inflammatory processes are linked with the nuclear factor-kappa B (NF-kappaB), we investigated in detail the effects of LPS on the NF-kappaB pathway and the postulated formation of Procollagen-Endotoxin-Complexes.
An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling.
Immuno-electron microscopy revealed that LPS physically interact with collagen type II in the extracellular matrix (ECM) and anti-collagen type II significantly reduced this interaction. BMS-345541 (a specific inhibitor of IkappaB kinase (IKK)) or wortmannin (a specific inhibitor of Phosphatidylinositol 3-kinase (PI-3K)) inhibited the LPS-induced degradation of the ECM and apoptosis in chondrocytes. This effect was completely inhibited by combining BMS-345541 and wortmannin. Furthermore, BMS-345541 and/or wortmannin suppressed the LPS-induced up-regulation of catabolic enzymes that mediate ECM degradation (matrix metalloproteinases-9, -13), cyclooxygenase-2 and apoptosis (activated caspase-3). These proteins are regulated by NF-kappaB, suggesting that the NF-kappaB and PI-3K pathways are involved in LPS-induced cartilage degradation. The induction of NF-kappaB correlated with activation of IBalpha kinase, IBalpha phosphorylation, IBalpha degradation, p65 phosphorylation and p65 nuclear translocation. Further upstream, LPS induced the expression of Toll-like receptor 4 (TLR4) and bound with TLR4, indicating that LPS acts through TLR4.
These results suggest that molecular associations between LPS/TLR4/collagen type II in chondrocytes up-regulate the NF-kappaB and PI-3K signalling pathways and activate pro-inflammatory activity.
Available from: Steffen Gay
- "Since RASF were able to destroy cartilage even in the absence of cellular and humoral immune responses, this study revealed that RASF are capable of maintaining their activated phenotype without further stimulation of the inflammatory environment in the synovium . RASF differ from healthy synovial fibroblasts by their morphology and an aberrant gene expression pattern . RASF are characterized by the expression of antiapoptotic molecules, protooncogenes and a lack of expression of tumor suppressor genes. "
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ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic inflammation of the joints with severe pain and swelling, joint damage and disability, which leads to joint destruction and loss of function. Despite extensive research efforts, the underlying cause for RA is still unknown and current therapies are more or less effective in controlling symptoms but still fail to cure the disease. In recent years, epigenetic modifications were found to strongly contribute to the development of RA by affecting diverse aspects of the disease and modifying gene expression levels and behavior of several cell types, first and foremost joint resident synovial fibroblasts (SF). RASF are the most common cell type at the site of invasion. Owing to their aggressive, intrinsically activated phenotype, RASF are active contributors in joint damage. RASF are characterized by their ability to secrete cytokines, chemokines and joint-damaging enzymes. Furthermore, these cells are resistant to apoptosis, leading to hyperplasia of the synovium. In addition, RASF have invasive and migratory properties that could lead to spreading of the disease to unaffected joints. Epigenetic modifications, including DNA methylation and post-translational histone modifications, such as histone (de)acetylation, histone methylation and histone sumoylation were identified as regulatory mechanisms in controlling aggressive cell activation in vitro and in disease outcome in animal models in vivo. In the last 5 years, the field of epigenetics in RA has impressively increased. In this review we consider the role of diverse epigenetic modifications in the development of RA, with a special focus on epigenetic modifications in RASF.
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