The AP-1 site and MMP gene regulation: what is all the fuss about? In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. NIH Tarner IH, Fathman CG. Dimitris Kontoyiannis 1 & George Kollias 1 Arthritis Research & Therapy volume 2, Article number: 342 (2000) Cite this article. Genes regulating the cell cycle are another option for novel therapeutic strategies. Aupperle K, Bennett B, Han Z, Boyle D, Manning A, Firestein G. NF-kappa B regulation by I kappa B kinase-2 in rheumatoid arthritis synoviocytes. Prominent examples include well-characterized cytokines like tumour necrosis factor alpha (TNFα) and interleukin (IL)-1, and also more recently described mediators like IL-15, IL-21R  and IL-22 . Rheumatoid arthritis progression mediated by activated synovial fibroblasts. 2007;9(6):223. doi: 10.1186/ar2337. The high expression of fos and jun, which are involved in the formation of the AP-1 transcription factor, appears to be mediated through upstream oncogenes like ras, scr and raf. The specific effects of different cytokines on the expression of individual MMPs, though, are highly variable and depend on the induced type of MMP, the cell type and the signal transduction pathway. Induction of urokinase-type plasminogen activator receptor by IL-1 beta. Dike LE, Farmer SR. This study was undertaken to evaluate the fibroblast-specific marker Hsp47 as a quantitative marker for SFs and to analyze its clinicopathologic correlates and evolution after anti-tumor necrosis factor α (anti-TNFα) therapy. In this review, we summarize and discuss recent research that highlights the role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis (RA). RA is a systemic disorder, and it is commonly accepted that it emerges from a variable combination of individual genetic predisposition, environmental factors (such as potential but unproven infectious agents) and dysregulated immune responses [2–5]. In industrialized countries, alterations in lifestyle and hygiene during the last century have shifted the sp… By activating intracellular signalling pathways, integrins mediate the contextual response of cells to the extracellular matrix. This notion is supported by reports on a number of RA patients who show progression of disease under TNF-blocking biologicals, even when combined with immunosuppressive drugs. Pundt N, Peters MA, Wunrau C, Strietholt S, Fehrmann C, Neugebauer K, Seyfert C, van Valen F, Pap T, Meinecke I. Arthritis Res Ther. Autoimmune disease: why and where it occurs. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. From these data, it can be concluded that RASFs are not only stimulated by pro-inflammatory cytokines but also by a cytokine-independent pathway through the activation of p38δ . Gustin JA, Ozes ON, Akca H, et al. 10-12 Also, extracellular matrix mineralization promotes podoplanin expression and drives osteocyte bone formation. Synovial fibroblasts (SFs) play an important role in the inflammatory process of the synovium. Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Baslund B, Tvede N, Danneskiold-Samsoe B, Peterson J, Peterson L, Schuurmann J. Distler JH, Jungel A, Huber LC, et al. Purpose of review Synovial fibroblasts continue to grow in prominence both as the subjects of research into the pathogenesis of rheumatoid arthritis and as novel therapeutic targets. Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of a cell surface-targeted plasmin inhibitor. Additionally synovial fibroblasts from the lining layer differ in biological and morphological characteristics to those of the sublining layer. | VCAM-1: Vascular cell adhesion molecule-1. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. In RASFs invading cartilage virtually no expression of PTEN was found, suggesting that the synovial hyperplasia in RA is due to defective apoptosis . Tissue degradation comprises the following major pathophysiological phenomena: growth, spreading and invasion of inflamed synovial tissue, and destruction of cartilage and bone. In this regard, macrophages, T cells and their respective cytokines play a pivotal role in RA. Takayanagi H, Iizuka H, Juji T, et al. Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. In a series of experiments, our group and others have demonstrated that activated RASFs produce inflammatory chemokines (e.g., IL-8, … Anchorage-independent growth of synoviocytes from arthritic and normal joints. Wang L, Zhao Q, Wang N, Ding Y, Kong L, Wang J. J Biol Res (Thessalon). Zwerina J, Hayer S, Tohidast-Akrad M, et al. The inflammation of the synovium can be observed in both of the two diseases. Systemic over-expression of TNF as achieved in the TNF transgenic mouse model (hTNFtg ) appears to be sufficient to initiate chronic synovitis, cartilage destruction and, finally, bone erosion . In particular, α3, α4 and α5 [formerly known as very late antigens (VLA) 3–5] are most prominently involved as the partner to β1 [29–31]. The expression rate was generally found to be low (<5%) but was increased in cells that were invading the articular cartilage, suggesting that p53 could be induced in cells at sites of cartilage invasion, thus rendering the cells a selective advantage . UDPGD: Uridine diphosphate glucose dehydrogenase. In industrialized countries, alterations in lifestyle and hygiene during the last century have shifted the spectrum of diseases from infectious to autoimmune-related disorders. Consequently synovial fibroblasts have lost their role as innocent bystanders in the pathogenesis of RA, and it has been understood that due to their active involvement in orchestrating cellular cross-talk and mediating intracellular cascades, they represent an important target for novel therapeutic approaches to the inhibition of joint destruction. Once activated, RASFs produce a variety of cytokines, chemokines and matrix-degrading enzymes that mediate the interaction with neighbouring inflammatory and endothelial cells and are responsible for the progressive destruction of articular cartilage and bone. These cells appear to be in the centre of the local pathogenic events, and there is growing evidence that activation of RASFs (e.g. Ishikawa H, Hirata S, Andoh Y, et al. Fine tuning of medium chain fatty acids levels increases fruity ester production during alcoholic fermentation. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3. These factors would then result in the attraction and accumulation of immune cells in the synovium and, through a stimulatory loop, to chronic inflammation. Hegewald AB, Breitwieser K, Ottinger SM, Mobarrez F, Korotkova M, Rethi B, Jakobsson PJ, Catrina AI, Wähämaa H, Saul MJ. A number of studies have demonstrated that RASFs show alterations in morphology and behaviour, including molecular changes in signalling cascades, apoptosis responses and in the expression of adhesion molecules as well as matrix-degrading enzymes. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. Your comment will be reviewed and published at the journal's discretion. In this context, the tumour suppressor p53 and its downstream molecule p21 have also been investigated. As a consequence, RASFs are no longer considered passive bystanders but active players in the complex intercellular network of RA. Full text. In addition, activation of NFκB increases the synthesis of the urokinase-type plasmin activator (uPa), which has been associated with activation of some of these enzymes [59, 78–80]. Marok R, Winyard PG, Coumbe A, et al. 2010 Apr;62(4):952-9. doi: 10.1002/art.27331. Various studies have revealed high transcription of immediate early genes in RASFs, for example egr-1 [35, 37] and fos [36, 38], as well as proto-oncogenes such as jun [36, 38] and myc . Such cytokines, together with growth factors, thus play an important role both in the continuous stimulation of RASFs towards aggressive behaviour as well as in the crosstalk between RASFs and other cell types in the synovium. Rheumatoid arthritis. 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