Rheumatoid Arthritis: Gay RE

Kuchen S, Pap T, Müller-Ladner U, Gay RE, Gay S. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #11072591 No free full text.

This publication has no abstract.

Karouzakis E, Gay RE, Gay S, Neidhart M. · Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland. · Nat Rev Rheumatol. · Pubmed #19412193 No free full text.

Abstract: Rheumatoid arthritis synovial fibroblasts (RASFs) are the effector cells of cartilage and bone destruction. These cells show an 'intrinsically' activated and aggressive phenotype that results in the increased production of matrix-degrading enzymes and adhesion molecules, and is conserved over long-term passage in vitro. The three main mechanisms of epigenetic control -- DNA methylation, histone modifications and microRNA activity -- interact in the development of the RASF phenotype. The extent of global DNA methylation is reduced in synoviocytes in situ and RASFs in vitro. In addition, histone hyperacetylation occurs and specific microRNAs are expressed in RASFs. Normal synovial fibroblasts cultured in a hypomethylating milieu acquire an activated phenotype similar to that of RASFs. These findings suggest that epigenetic control, in particular the control of DNA methylation, is deficient in RASFs. Genome-wide analyses of the epigenome will enable the detection of additional genes involved in the pathogenesis of rheumatoid arthritis, the identification of epigenetic biomarkers, and potentially the development of a therapeutic regimen that targets activated RASFs.

Moritz F, Distler O, Ospelt C, Gay RE, Gay S. · Center of Experimental Rheumatology, Department of Rheumatology, University of Zurich, Switzerland. · Nat Clin Pract Rheumatol. · Pubmed #16932675 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by systemic inflammation and joint destruction. Novel therapies have emerged during the past decade, marking a new era in the treatment of RA. Meanwhile, in vivo and in vitro gene-transfer studies have provided valuable insights into mechanisms of disease pathogenesis. Advanced gene-delivery techniques and animal models promise further progress in RA research and the development of novel therapeutic strategies for this disease. In this article we provide an overview of the wide spectrum of potential targets that have been identified so far, discuss currently available gene-transfer methods, and outline the barriers that need to be overcome for these approaches to be successfully applied in daily practice.

Müller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. · Department of Internal Medicine and Rheumatology, Justus-Liebig University Giessen, Kerckhoff-Clinic, Bad Nauheim, Germany. · Nat Clin Pract Rheumatol. · Pubmed #16932639 No free full text.

Abstract: Rheumatoid arthritis is a complex systemic disease that ultimately leads to the progressive destruction of articular and periarticular structures. Novel data indicate that the innate immune system (through activation of Toll-like receptors) is involved in articular pathophysiology, including the recruitment of inflammatory cells, and that periarticular factors such as adipocytokines contribute to the perpetuation of joint inflammation. The deleterious process of joint destruction is mediated by intracellular signaling pathways involving transcription factors, such as nuclear factor kappaB, cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules. Advances in molecular biology techniques have identified T-cell-independent and B-cell-independent pathways that operate at different stages of the disease. Cytokine-independent pathways appear to be responsible for maintaining basic disease activity that is not affected by currently available therapies. Using this knowledge in combination with gene-transfer and gene-silencing approaches, bench-to-bedside strategies will be developed, thus enabling the creation of novel treatments for rheumatoid arthritis.

Karouzakis E, Neidhart M, Gay RE, Gay S. · Center of Experimental Rheumatology, University Hospital Zurich, Switzerland. · Immunol Lett. · Pubmed #16824621 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with joint destruction. Synovial fibroblasts are key players in this pathological process. They favorise a pro-inflammatory environment in the synovial tissue, interact with the immune system and regulate the differentiation of monocytes into osteoclasts. Synovial hyperplasia is another characteristic of RA, reflecting not only an imbalance between proliferation and apoptosis, but also the migration of cells into the synovial tissue. Gene transfer experiments have been used as important tools for the understanding of molecular and cellular changes that characterize the activated RA synovial fibroblasts. Activated synovial fibroblasts can invade cartilage and bone. Synovial activation is driven by cytokines, such as TNFalpha and IL-1, as well as IL-15, 16, 17, 18, 22, 23, but also by cytokine-independent mechanisms that involve the innate immune system (i.e. TLRs), a unique communication network of microparticles and epigenetic changes (e.g. L1 retroelements).

Moritz F, Distler O, Gay RE, Gay S. · Zentrum für Experimentelle Rheumatologie, Rheumaklinik und Institut für Physikalische Medizin, Universitätsspital Zürich. · Dtsch Med Wochenschr. · Pubmed #16817105 No free full text.

This publication has no abstract.

Stanczyk J, Ospelt C, Gay RE, Gay S. · Center of Experimental Rheumatology and World Health Organization Collaborating Center for Molecular Biology and Novel Therapeutic Strategies, Department of Rheumatology, University Hospital Zurich, Switzerland. · Curr Opin Rheumatol. · Pubmed #16582690 No free full text.

Abstract: PURPOSE OF REVIEW: Modern molecular biology offers a unique opportunity to gain a comprehensive picture of gene expression in a disease state. This review presents recent findings in the field of synovial fibroblast biology contributing to knowledge of the pathogenesis of rheumatoid arthritis. RECENT FINDINGS: Recently it has become apparent that innate immune response pathways play a critical role in driving synovial activation and contribute significantly to the turnover of leukocytes in the synovial compartment. In addition, microparticles have been identified as a new class of potent mediators, broadening the known spectrum of cell-derived modulators in the joint. Numerous research groups gained new insights into detailed molecular mechanisms leading to the invasiveness of rheumatoid arthritis synovial fibroblasts, the disturbance in the regulation of apoptosis, and synovial cell-cell and cell-matrix interactions. SUMMARY: The key role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis has been highlighted by the fact that these cells not only are the main executors of cartilage and bone destruction but also modulate numerous interactions in rheumatoid joints. Moreover, it has become evident that integration of a large body of information is indispensable to get a comprehensive outlook on synovial activation in the pathology of rheumatoid arthritis.

Huber LC, Distler O, Gay RE, Gay S. · Center of Experimental Rheumatology, WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, University of Zurich, University Hospital Zurich, Gloriastr. 23, CH-8091 Zurich, Switzerland. · Adv Drug Deliv Rev. · Pubmed #16574269 No free full text.

Abstract: Oligodeoxynucleotides, ribozymes, and RNA interference make part of the antisense strategy, a new tool proposed to conquer cancer, viral infections, as well as cardiovascular and rheumatic diseases. The silencing effect of antisense strategies is both highly specific and potent - and only requires that the sequence of the target RNA is known. However, so far neither RNAi nor ribozymes have been approved for clinical use and only a single antisense agent is on the market. In the context of degenerative joint diseases, experimental data in the field of antisense strategies are still rare. Several studies from rheumatoid arthritis (RA), an inflammatory condition that leads to the progressive destruction of cartilage and bone within affected joints, however revealed promising results and taught us important lessons that might also be useful in therapeutic approaches for osteoarthritis (OA). To introduce these therapies in clinical practice, however, several hurdles still have to be overcome.

Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. · Center of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 23CH-8091 Zürich, Switzerland. · Rheumatology (Oxford). · Pubmed #16567358 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune-disease of unknown origin that primarily affects the joints and ultimately leads to their destruction. The involvement of immune cells is a general hallmark of autoimmune-related disorders. In this regard, macrophages, T cells and their respective cytokines play a pivotal role in RA. However, the notion that RA is a primarily T-cell-dependent disease has been strongly challenged during recent years. Rather, it has been understood that resident, fibroblast-like cells contribute significantly to the perpetuation of disease, and that they may even play a role in its initiation. These rheumatoid arthritis synovial fibroblasts (RASFs) constitute a quite unique cell type that distinguishes RA from other inflammatory conditions of the joints. 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. These changes appear to reflect a stable activation of RASFs, which occurs independently of continuous exogenous stimulation. As a consequence, RASFs are no longer considered passive bystanders but active players in the complex intercellular network of RA.

Senolt L, Grigorian M, Lukanidin E, Michel BA, Gay RE, Gay S, Pavelka K, Neidhart M. · Center of Experimental Rheumatology, Univ Hosp Zürich, Gloriastrasse 25, CH-8091 Zürich, Switzerland. · Autoimmun Rev. · Pubmed #16431343 No free full text.

Abstract: S100A4 (Mts1) belongs to the S100 family of calcium binding proteins, which are involved in diverse biological regulatory activities. An association between S100A4 and tumor progression has been demonstrated in several studies. S100A4 binds to distinct intracellular target proteins and regulates specific functions involved in tumor progression such as cell motility, proliferation and apoptosis as well as remodelling of the extracellular matrix. Once released from the tumor or tumor-activated stromal cells, it may influence certain functions of target cells towards a more aggressive phenotype. Extracellular S100A4 has been demonstrated to contribute to angiogenesis and the increased production of matrix-degrading enzymes by both endothelial and tumor cells. Moreover, S100A4 might be responsible for TCRgammadelta T-cell mediated lysis and negative regulation of matrix mineralization. Increased expression of S100A4 mRNA has recently been found in proliferating rheumatoid arthritis synovial fibroblasts and synovial tissues from rheumatoid arthritis patients. Synovial hyperplasia in rheumatoid arthritis consists of inflammatory cells and activated synovial lining cells which contribute to the progressive destruction of the joints during the disease. Since several phenomena are similar between rheumatoid arthritis and malignant tumors it can be hypothesized that S100A4 contributes to the invasive and tumor-like behavior of rheumatoid arthritis synovium.

Ospelt C, Neidhart M, Gay RE, Gay S. · University Hospital, Zurich, Switzerland. · Arthritis Rheum. · Pubmed #16052564 links to  free full text

This publication has no abstract.

Tarner IH, Härle P, Müller-Ladner U, Gay RE, Gay S. · Department of Internal Medicine I, University Hospital Regensburg, D-93042 Regensburg, Germany. · Best Pract Res Clin Rheumatol. · Pubmed #15588969 No free full text.

Abstract: Rheumatoid arthritis is a systemic inflammatory disease that, by definition, can affect all parts of the human body, including severe complications such as uveitis/episcleritis and vasculitis of the heart, lungs, kidneys and the central and peripheral nervous systems. Its primary and by far the most common manifestations, however, affect the joints and are characterised by inflammatory reactions and activation of the synovial lining tissue and associated structures, the latter resulting in tenovaginitis and rheumatoid nodules. As all pathophysiological mechanisms are based on pathways that are inherent in the different components of a joint, it is necessary to examine the unique features of normal synovium prior to analysing disease-specific pathways. This chapter will therefore describe the physiological structure of the synovium and the inflammatory pathology of rheumatoid synovitis in early and chronic stages of the disease.

Ospelt C, Kyburz D, Pierer M, Seibl R, Kurowska M, Distler O, Neidhart M, Muller-Ladner U, Pap T, Gay RE, Gay S. · WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Clinic for Rheumatology, University Hospital, Gloriastrasse 25, CH-8091 Zurich, Switzerland. · Ann Rheum Dis. · Pubmed #15479881 links to  free full text

This publication has no abstract.

Huber LC, Pap T, Müller-Ladner U, Gay RE, Gay S. · WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies, Department of Rheumatology, University Hospital, Gloriastrasse 25, CH-8091 Zurich, Switzerland. · Curr Rheumatol Rep. · Pubmed #15355741 No free full text.

This publication has no abstract.

Ospelt C, Neidhart M, Gay RE, Gay S. · Center of Experimental Rheumatology, University Hospital, Gloriastrasse 25, CH-8091 Zurich, Switzerland. · Front Biosci. · Pubmed #15353290 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive articular damage. Activated cells of the synovium produce pro-inflammatory and matrix-degrading effector molecules, which maintain the inflammation and lead to the destruction of the involved joints. In addition to macrophages and T- and B-cells, fibroblast-like synoviocytes must be considered key cells in driving the pathological processes. They can be distinguished by their transformed-appearing phenotype and their invasion into adjacent cartilage and bone. Synovial activation is driven by pro-inflammatory cytokines as well as cytokine independent pathways including endogenous retroviral elements and Toll-like receptors (TLR). These pathways are connected by a complex network of autocrine and paracrine acting factors. Another feature of RA synovium is hyperplasia of the lining layer, which results from increased proliferation and decreased apoptosis of synovial fibroblasts. Thanks to new techniques in basic research, novel insights into the cellular and molecular mechanisms of the pathogenesis of RA were gained and led to the development of new, specific therapeutic strategies.

Neumann E, Gay RE, Gay S, Müller-Ladner U. · Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. · Curr Opin Rheumatol. · Pubmed #15103251 No free full text.

Abstract: PURPOSE OF REVIEW: Successful analysis of the pathophysiology of rheumatoid arthritis requires the functional understanding of interactions between different cell types and the cell matrix, intracellular signaling pathways, as well as between cartilage, bone, and synovium in rheumatoid arthritis. During the review period, molecular biology has provided and used a growing number of tools to screen the genome such as gene and protein chips, haplotype analysis, and single nucleotide polymorphism analysis, resulting in various novel findings with considerable impact on the overall understanding of rheumatoid arthritis. RECENT FINDINGS: Key issues that have been addressed and elucidated by numerous research groups are the regulation and modulation of synovial fibroblast metabolism and activation by proinflammatory cytokines and chemokines. In addition, examination of adhesion processes and neoangiogenesis has revealed new insights into the interaction network between rheumatoid synovial fibroblasts and the surrounding matrix and cells. Finally, a more detailed view of activation of these fibroblasts has been obtained by analysis of the molecular balance between cellular activation and regulation of apoptosis. SUMMARY: Although high throughput molecular analysis methods provided an ample amount of novel data, it needs to be stressed that a one-method approach of gene expression (eg, by array analysis) is not sufficient to validate the gene/gene product as a new therapeutic target. Therefore, the next steps are the so-called functional genomics or functionomics, which intend to reveal relations between the obtained data and to unveil their interactions for a better understanding of the pathogenesis and the mechanisms that are operative in rheumatoid arthritis.

Pierer M, Müller-Ladner U, Pap T, Neidhart M, Gay RE, Gay S. · WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital, Gloriastrasse 25, 8091, Zurich, Switzerland. · Springer Semin Immunopathol. · Pubmed #12904892 No free full text.

Abstract: The hallmark of rheumatoid arthritis (RA) is progressive destruction of the joints, preceded and accompanied by synovial hyperplasia and chronic inflammation. Spontaneous and induced animal models of RA reflect predominantly the inflammatory aspects of the disease. To reproduce the destruction of cartilage and bone mediated by an activated synovium, it was desirable to develop models that allow the dissection of cellular and molecular components derived from human tissue. The SCID mouse co-implantation model of human RA focuses on RA synovial fibroblasts (RA-SF) and their role in cartilage destruction. The model has provided the best evidence that RA-SF contribute significantly to matrix degradation, even in the absence of human lymphocytes and macrophages, since highly purified RA-SF invade the co-implanted normal human cartilage. Moreover, it became clear that they maintained their aggressive phenotype over long periods of time, particularly at sites of invasion into the co-implanted human cartilage. Targeting different signaling molecules, cytokines and matrix-degrading enzymes by soluble receptors, antagonists or negative mutants in the SCID mouse model of RA has implicated many of them in the mechanisms leading to cartilage destruction. However, since inhibition of a single molecule or pathway is not sufficient to inhibit the aggressive behavior of RA-SF it appears necessary to co-express in the synoviocytes genes for two or even more antagonists of e.g. cytokines, matrix-degrading enzymes or molecules interfering specifically with signaling pathways involved in the apoptosis of RA-SF. Based on the recent observation that the L1 (line-1) endogenous retroviral element appears responsible for the cytokine- independent activation via the MAPK p38delta, the current understanding of disease pathogenesis suggests that both the cytokine-dependent as well as the cytokine-independent pathways of joint destruction must be inhibited. Modulation of both pathways by gene transfer approaches in the SCID mouse model is a feasible method aimed at identifying novel targets for the prevention of cartilage destruction in RA.

Müller-Ladner U, Pap T, Gay RE, Gay S. · Department of Internal Medicine I, University of Regensburg, FJS-Allee 11, D-93042 Regensburg, Germany. · Expert Opin Biol Ther. · Pubmed #12831364 No free full text.

Abstract: Inhibiting key pathogenic processes within the rheumatoid synovium is a most attractive goal to achieve, and the number of potential intra- and extracellular pathways operative in rheumatoid arthritis (RA) that could be used for a gene therapy strategy is increasing continuously. Gene transfer or gene therapy might also be one of the approaches to solve the problem of long-term expression of therapeutic genes, in order to replace the frequent application of recombinant proteins, in the future. However, at present, gene therapy has not reached a realistic clinical stage, which is mainly due to severe side effects in humans, the complexity of RA pathophysiology and the current state of available gene transfer techniques. On the other hand, novel gene delivery systems are not restricted to vectors or certain types of cells, as mobile cells including macrophages, dendritic cells, lymphocytes and multipotent stem cells can also be used as smart gene transfer vehicles. Moreover, the observation in animal models that application of viral vectors into a joint can exert additional therapeutic effects in nearby joints might also facilitate the transfer from animal to human gene therapy. Future strategies will also examine the potential of novel long-term expression vectors such as lentiviruses and cytomegalovirus (CMV)-based viruses as a basis for future clinical trials in RA.

Gay S, Kuchen S, Gay RE, Neidhart M. · WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital, Gloriastrasse 25, CH-8091 Zurich, Switzerland. · Ann Rheum Dis. · Pubmed #12379633 links to  free full text

This publication has no abstract.

Müller-Ladner U, Gay RE, Gay S. · Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany. · Curr Rheumatol Rep. · Pubmed #12010604 No free full text.

Abstract: The evaluation of molecular pathways has revealed novel insights into the pathophysiology of rheumatoid arthritis in the last several years. Gene transcription factors such as nuclear factor kB (NFkB) are activated by extracellular signals or cell-to-cell interactions that are converted into intracellular activation signals through receptor molecules located in the cell membrane. The number of known genes being translated after NFkB activation is increasing steadily. These genes includes cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules. Because many of these genes are part of the pathogenesis of RA, there is considerable interest in the evaluation of the synovium-specific effects of NFkB to unveil its potential for future therapeutic strategies. The goal is to evolve these strategies from the therapies that have a wide spectrum of effects and side effects into rheumatoid arthritis-specific therapies designed to inhibit distinct molecular pathways within the synovium.

Pap T, Gay RE, Müller-Ladner U, Gay S. · Division of Experimental Rheumatology, Center of Internal Medicine, University Hospital Magdeburg, Germany. · Arthritis Res. · Pubmed #11879532 links to  free full text

Abstract: Synovial fibroblasts (SFs) have become a major target for ex vivo gene transfer in rheumatoid arthritis (RA), but efficient transduction of RA-SFs still is a major problem. The low proliferation rate and heterogeneity of RA-SFs, together with their lack of highly specific surface receptors, have hampered a more extensive application of this technique. Improving transduction protocols with conventional viral vectors, therefore, as well as developing novel strategies, such as alternative target cells, and novel delivery systems constitute a major challenge. Recent progress in this field will lead to the achievement of high transgene expression, and will facilitate the use of gene transfer in human trials.

Seemayer CA, Distler O, Kuchen S, Müller-Ladner U, Michel BA, Neidhart M, Gay RE, Gay S. · WHO-Collaborating Center for Molecular Biology and Novel Therapeutic Strategies of Rheumatic Diseases, Department of Rheumatology, University Hospital Zürich, Gloriastrasse 25, 8091 Zürich, Switzerland. · Z Rheumatol. · Pubmed #11759230 No free full text.

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is mainly characterized by synovial hyperplasia, pathological immune phenomena and progressive destruction of the affected joints. Various cell types are involved in the pathogenesis of RA including T cells, antigen presenting cells, and endothelial cells. Recent experimental evidence suggests that the CD40/CD154 system might play an important role in the development of RA. Our experimental approach focuses on RA synovial fibroblasts (RA-SF) that are able to destroy articular cartilage independent of inflammation. To elucidate the specific role of those cells in RA pathophysiology the following questions are currently addressed: 1. Which mechanisms do activate the RA-SF? 2. How do the activated RA-SF attach to the cartilage? 3. How do RA-SF destroy cartilage and bone? Which mechanisms do activate the RA-SF? The process of activation is poorly understood. It is unclear, how far the synovial hyperplasia of RA resembles tumor diseases. Along this line some contradictory results exist concerning the role of the tumor suppressor protein p53. Some investigations could show the expression of p53 in the synovial lining including p53 mutations in RA synovium and in RASF, while other research groups could not confirm these data. Our group has demonstrated that the tumor suppressor PTEN was less expressed in the synovial lining of RA than in normal synovium, but no PTEN mutations could be found in the RA-SF. In addition, the in vivo and in vitro expression of the anti-apoptotic molecule sentrin suggests a functional resistance of RA-SF to undergo apoptosis. Although it is still unclear, whether certain viruses or viral elements are involved in the pathogenesis of RA (cause, consequence or coincidence?), certain viruses could play a role in the pathogenesis of RA. The endogenous retroviral element L1 was found to be expressed in the synovial lining, at sites of invasion as well as in RA-SF grown in vitro. Moreover, the data indicate that after the initial activation of L1 downstream molecules such as the SAP kinase 4, the met-protoonocogene and the galectin-3 binding protein are upregulated. How do the activated RA-SF attach to the cartilage? It has been suggested that integrins mediate the attachment of RA-SF to fibronectin rich sites of cartilage. Intriguingly, other adhesion molecules such as the vascular cellular adhesion molecule-1 (VCAM) and CS-1, a splice variant of fibronectin, are synthesized by RA-SF. By binding to these adhesion molecules, lymphocytes that express the integrin VLA-4 could be stimulated and thereby maintain the inflammatory process. Osteopontin is an extracellular matrix protein, which is associated with matrix adhesion and metastasis in tumors. In RA synovium, osteopontin was detectable in the synovial lining and at sites of invasion. How do RA-SF destroy cartilage and bone? The destruction of cartilage and bone in RA is mediated by matrix metalloproteinases (MMPs) and cathepsins. MMPs exist as secreted and as membrane bound forms. In vitro models are being developed to simulate the invasive process of RA-SF. In an in vitro model developed in our laboratory, the treatment of RA-SF with anti-CD44 or anti-interleukin-1 (IL-1) minimized matrix degradation of RA-SF. On the other hand, co-culture of RA-SF and U937 cells as well as application of interleukin-1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF alpha) increased the invasiveness of RA-SF. Gene transfer of bovine pancreas trypsin inhibitor (BPMI) or interleukin-10 (IL-10) reduced the invasion of RA-SF, while transduction of interleukin-1 receptor antagonist (IL-1Ra) was chondroprotective. Double gene transfer of IL-10 and IL-1Ra resulted in both inhibition of invasion and chondroprotection.

Pap T, Müller-Ladner U, Gay RE, Gay S. · Department of Rheumatology, University Hospital, Zürich, Switzerland. · Arthritis Res. · Pubmed #11094449 links to  free full text

Abstract: There is growing evidence that activated synovial fibroblasts, as part of a complex cellular network, play an important role in the pathogenesis of rheumatoid arthritis. In recent years, significant progress has been made in elucidating the specific features of these fibroblasts. It has been understood that although macrophage and lymphocyte secreted factors contribute to their activation, rheumatoid arthritis synovial fibroblasts (RA-SFs) do not merely respond to stimulation by pro-inflammatory cytokines, but show a complex pattern of molecular changes also maintained in the absence of external stimulation. This pattern of activation is characterized by alterations in the expression of regulatory genes and signaling cascades, as well as changes in pathways leading to apoptosis. These together result in the upregulation of adhesion molecules that mediate the attachment of RA-SFs to the extracellular matrix and in the overexpression of matrix degrading enzymes that mediate the progressive destruction of the joints. In addition, activated RA-SFs exert specific effects on other cell types such as macrophages and lymphocytes. While the initiating step in the activation of RA-SFs remains elusive, several key pathways of RA-SF activation have been identified. However, there is so far no single, specific marker for this phenotype of RA-SF. It appears that activated RA-SFs are characterized by a set of specific properties which together lead to their aggressive behavior.

Pap T, Gay RE, Gay S. · WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies for Rheumatic Diseases, Department of Rheumatology, University Hospital, Zurich, Switzerland. · Curr Opin Rheumatol. · Pubmed #10803750 No free full text.

Abstract: In the last few years, several novel strategies have been proposed for the treatment of rheumatoid arthritis (RA). Among them, gene therapy is considered a promising concept bearing the potential of highly specific targeting of relevant pathomechanisms. Early studies using gene transfer focused mainly on studying disease mechanisms, whereas recent research has put potential clinical applications to the forefront of attention. This has provided new answers to the question of how to deliver genes into the rheumatoid synovium as well as which pathways to target. Thus, significant progress has been made in the continued development of viral systems, including retro- and adenoviruses, as well as in the exploration of novel tools such as herpes virus-based systems or liposomes in combination with viral fusion proteins. When potential targets for gene transfer in RA are considered, two strategies have emerged: the first focuses on the delivery of secreted proteins, mainly cytokines and cytokine receptors, to inhibit inflammation in arthritic joints. Based on our growing knowledge about the pathogenesis of RA, however, there has also been substantial progress in exploring approaches that aim at interfering specifically with signaling pathways involved in the activation and apoptosis of synovial cells. The data from recent studies indicate the ability to selectively target specific disease processes by the differential expression of therapeutic genes in varying cell types and at different stages of disease, thus demonstrating the potential of gene transfer as an arthritis therapy.

Müller-Ladner U, Gay RE, Gay S. · Department of Internal Medicine I, University of Regensburg, Germany. · Curr Opin Rheumatol. · Pubmed #10803747 No free full text.

Abstract: The evaluation of molecular pathways has revealed various novel insights into rheumatoid arthritis pathophysiology during the past year. In addition, there is an increasing tendency toward analysis not merely of a single mechanism but rather of data addressing a substantial part of the cascade of events leading to cellular activation. Because synovial fibroblasts are key cells involved in joint destruction, this review outlines the events that trigger or inhibit the crucial pathways leading to their aggressive behavior. Major topics include cellular and humoral interactions (frequently modulated by cytokines), intracellular signaling and upregulation of gene transcription, and the deleterious effects on articular homeostasis.