Genomic Responses of Mouse Synovial Fibroblasts During Tumor Necrosis Factor–Driven Arthritogenesis Greatly Mimic Those in Human Rheumatoid Arthritis

Ntougkos, Evangelos; Chouvardas, Panagiotis; Roumelioti, Fani; Ospelt, Caroline; Frank-Bertoncelj, Mojca; Filer, Andrew; Buckley, Christopher D.; Nikolaou, Christoforos; Kollias, George

doi:10.1002/art.40128

Cited by 34 publications

(47 citation statements)

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“…is used . However, a closer look at the data of the present study reveals some interesting novel aspects. As the most studied epigenetic change in RA has been DNA methylation, the data confirm a hypomethylated profile, which is consistent with previous studies of human RA synovial fibroblasts .…”

mentioning

confidence: 76%

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Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

Müller‐Ladner

Neumann

2017

Arthritis & Rheumatology

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mentioning

confidence: 76%

“…From our point of view, Ntougkos and colleagues' work reveals interesting features that puts several pieces of the RA puzzle into place. First, it illustrates the obviously tight link between one of the key proinflammatory and prodestructive molecules in RA, TNF, and one of the cell types that drive joint destruction, the synovial fibroblast.…”

mentioning

confidence: 92%

Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

Müller‐Ladner

Neumann

2017

Arthritis & Rheumatology

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“…Mouse FLS cultures. FLS were isolated by digesting interphalangeal joint synovium with 1 mg/ml of collagenase IV (Sigma‐Aldrich) for 2 hours at 37°C . Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum (FCS; Invitrogen) and used at passage 4.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse FLS cultures. FLS were isolated by digesting interphalangeal joint synovium with 1 mg/ml of collagenase IV (Sigma-Aldrich) for 2 hours at 37°C (24 Histology and RNA in situ hybridization. Paraffinembedded sections of mouse limbs were generated after tissue fixation in 4% paraformaldehyde for 48 hours, followed by demineralization in 0.5M EDTA (pH 7.5) for 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

Bhattaram

Muschler

Wixler

et al. 2018

Arthritis & Rheumatology

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Objectives Fibroblast-like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer-like and aggressively contribute to joint degeneration in inflammatory arthritis. Here we asked whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions. Methods We inactivated the SOXC genes in FLS of adult mice and studied consequences on joint homeostasis and tumor necrosis factor-alpha (TNFα)-induced arthritis. We used primary cells and synovial biopsies from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins. Results Postnatal inactivation of the SOXC genes had no major consequence on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNFα. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNFα on FLS aggressiveness, including increased cell survival and migration. SOXC RNA levels were unchanged by TNFα and other pro-inflammatory cytokines, but their proteins were strongly stabilized and able to potentiate the TNFα-induced upregulation of genes involved in FLS transformation. Substantiating the human disease relevance of these findings, the SOXC protein, but not RNA levels, were significantly higher in inflamed than non-inflamed synovium from arthritic patients. Conclusion SOXC proteins are targets and pivotal mediators of pro-inflammatory cytokines during FLS transformation in arthritic diseases. Their targeting could thus improve current strategies to treat these and possibly other inflammatory diseases.

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“…Sustained expression of TNF can have devastating effects as is evident in transgenic animal models of inflammatory diseases (31). We have recently analyzed the transcriptome dynamics of fibroblasts originating from such an animal model (32) to show that a gradual activation of inflammatory and immune-related pathways accurately mirrors the phenotype of progressive inflammatory polyarthritis. While valuable from the biomedical viewpoint however, in vivo approaches do not allow the precise modeling of gene regulation due to cellular cross-talk.…”

Section: Introductionmentioning

confidence: 99%

Monitoring the prolonged TNF stimulation in space and time with topological-functional networks

Papoudas

Papanikolaou

Nikolaou

2019

Preprint

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Genes in linear proximity often share regulatory inputs, expression and evolutionary patterns, even in complex eukaryote genomes with extensive intergenic sequences. Gene regulation, on the other hand, is effected through the co-ordinated activation (or suppression) of genes participating in common biological pathways, which are often transcribed from distant loci. Existing approaches for the study of gene expression focus on the functional aspect, taking positional constraints into account only marginally.In this work we propose a novel concept for the study of gene expression, through the combination of topological and functional information into bipartite networks. Starting from genome-wide expression profiles, we define extended chromosomal regions with consistent patterns of differential gene expression and then associate these domains with enriched functional pathways. By analyzing the resulting networks in terms of size, connectivity and modularity we can draw conclusions on the way genome organization may underlie the gene regulation program.We implement our approach in a detailed RNASeq profiling of sustained TNF stimulation of mouse synovial fibroblasts. Bipartite network analysis suggests that the cytokine response set by TNF, progresses through two distinct transitions. An early generalization of the inflammatory response, marked by an increase in related functions and high connectivity of corresponding genomic loci, that is followed by a late shutdown of immune functions and the redistribution of expression to developmental and cell adhesion pathways and distinct chromosomal regions.Our results suggest that the incorporation of topological information may provide additional insights in the underlying topological constraints that are shaping gene expression.

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Genomic Responses of Mouse Synovial Fibroblasts During Tumor Necrosis Factor–Driven Arthritogenesis Greatly Mimic Those in Human Rheumatoid Arthritis

Cited by 34 publications

References 50 publications

Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

Editorial: Tumor Necrosis Factor–Transgenic Mice: Close Enough to Human Epigenetics?

Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

Monitoring the prolonged TNF stimulation in space and time with topological-functional networks

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