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author:("armata, Maria")
1.  Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis 
Synovial fibroblasts from patients and mice with arthritis express autotaxin, and ablation of autotaxin in fibroblasts ameliorates disease.
Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX expression from SFs was induced by TNF, and LPA induced SF activation and effector functions in synergy with TNF. Conditional genetic ablation of ATX in mesenchymal cells, including SFs, resulted in disease attenuation in animal models of arthritis, establishing the ATX/LPA axis as a novel player in chronic inflammation and the pathogenesis of arthritis and a promising therapeutic target.
PMCID: PMC3348105  PMID: 22493518
2.  Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases 
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.
PMCID: PMC2271010  PMID: 18250193
3.  Generation and Characterization of p38β (MAPK11) Gene-Targeted Mice 
Molecular and Cellular Biology  2005;25(23):10454-10464.
p38 mitogen-activated protein kinases (MAPKs) are activated primarily in response to inflammatory cytokines and cellular stress, and inhibitors which target the p38α and p38β MAPKs have shown potential for the treatment of inflammatory disease. Here we report the generation and initial characterization of a knockout of the p38β (MAPK11) gene. p38β−/− mice were viable and exhibited no apparent health problems. The expression and activation of p38α, ERK1/2, and JNK in response to cellular stress was normal in embryonic fibroblasts from p38β−/− mice, as was the activation of p38-activated kinases MAPKAP-K2 and MSK1. The transcription of p38-dependent immediate-early genes was also not affected by the knockout of p38β, suggesting that p38α is the predominant isoform involved in these processes. The p38β−/− mice also showed normal T-cell development. Lipopolysaccharide-induced cytokine production was also normal in the p38β−/− mice. As p38 is activated by tumor necrosis factor, the p38β−/− mice were crossed onto a TNFΔARE mouse line. These mice overexpress tumor necrosis factor, which results in development symptoms similar to rheumatoid arthritis and inflammatory bowel disease. The progression of these diseases was not however moderated by knockout of p38β. Together these results suggest that p38α, and not p38β, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38β during the development of p38 inhibitors.
PMCID: PMC1291241  PMID: 16287858
5.  Cytoskeletal Rearrangements in Synovial Fibroblasts as a Novel Pathophysiological Determinant of Modeled Rheumatoid Arthritis 
PLoS Genetics  2005;1(4):e48.
Rheumatoid arthritis is a chronic inflammatory disease with a high prevalence and substantial socioeconomic burden. Despite intense research efforts, its aetiology and pathogenesis remain poorly understood. To identify novel genes and/or cellular pathways involved in the pathogenesis of the disease, we utilized a well-recognized tumour necrosis factor-driven animal model of this disease and performed high-throughput expression profiling with subtractive cDNA libraries and oligonucleotide microarray hybridizations, coupled with independent statistical analysis. This twin approach was validated by a number of different methods in other animal models of arthritis as well as in human patient samples, thus creating a unique list of disease modifiers of potential therapeutic value. Importantly, and through the integration of genetic linkage analysis and Gene Ontology–assisted functional discovery, we identified the gelsolin-driven synovial fibroblast cytoskeletal rearrangements as a novel pathophysiological determinant of the disease.
Rheumatoid arthritis (RA) is a chronic destructive disease that affects 1–3% of the general population, exacting substantial personal, social, and economic costs. Current treatments alleviate the symptoms and offer immediate relief for many patients but do not cure the disease. While the cause of the disease remains poorly understood, the completion of the Human Genome Project and the emergence of functional genomics and high-throughput technologies offer intriguing new possibilities. For example, expression profiling creates a molecular fingerprint of the disease status by quantifying the expression levels of thousand of genes simultaneously. Similarly, reverse genetics (the genetic modification of a particular gene in search of its function) allow for the creation of animal models of disease. To discover novel genes and/or cellular pathways involved in the development of the disease, the authors used two methods in an animal model of RA for large-scale expression profiling. They identified a large number of genes and molecular processes that are deregulated in the disease. Using this information, the authors described pathophysiologic determinants of RA and created a unique list of disease modifiers of potential therapeutic value.
PMCID: PMC1270006  PMID: 16254600
6.  Genetic Dissection of the Cellular Pathways and Signaling Mechanisms in Modeled Tumor Necrosis Factor–induced Crohn's-like Inflammatory Bowel Disease 
The Journal of Experimental Medicine  2002;196(12):1563-1574.
Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (TnfΔAREmouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon γ and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.
PMCID: PMC2196068  PMID: 12486099
MAPK/SAPK; targeted mutants; CD8+ lymphocytes; apoptosis; intestine
7.  Functional analysis of an arthritogenic synovial fibroblast 
Arthritis Research & Therapy  2003;5(3):R140-R157.
Increasing attention has been directed towards identifying non-T-cell mechanisms as potential therapeutic targets in rheumatoid arthritis. Synovial fibroblast (SF) activation, a hallmark of rheumatoid arthritis, results in inappropriate production of chemokines and matrix components, which in turn lead to bone and cartilage destruction. We have demonstrated that SFs have an autonomous pathogenic role in the development of the disease, by showing that they have the capacity to migrate throughout the body and cause pathology specifically to the joints. In order to decipher the pathogenic mechanisms that govern SF activation and pathogenic potential, we used the two most prominent methods of differential gene expression analysis, differential display and DNA microarrays, in a search for deregulated cellular pathways in the arthritogenic SF. Functional clustering of differentially expressed genes, validated by dedicated in vitro functional assays, implicated a number of cellular pathways in SF activation. Among them, diminished adhesion to the extracellullar matrix was shown to correlate with increased proliferation and migration to this matrix. Our findings support an aggressive role for the SF in the development of the disease and reinforce the perspective of a transformed-like character of the SF.
PMCID: PMC165045  PMID: 12723986
fibroblast; gene expression; migration; rheumatoid arthritis; tumor necrosis factor

Results 1-7 (7)