FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis
| Autor: | Boris V. Skryabin, C Cromme, Adelheid Korb-Pap, Viktor Wixler, Eugen Retser, Christina Koers-Wunrau, Thomas Pap, Yannis Sotsios, Lars Meyer, Dominique Baeten, Rhonda Bassel-Duby, Katja Mühlenberg, Kurt Redlich, Stephan Ludwig, Neil Smyth, Jessica Bertrand, Paul P. Tak, Birgit Niederreiter |
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| Přispěvatelé: | Amsterdam institute for Infection and Immunity, Clinical Immunology and Rheumatology |
| Rok vydání: | 2014 |
| Předmět: |
Necrosis
Inflammatory arthritis Transgene Immunoblotting LIM-Homeodomain Proteins Immunology Muscle Proteins Mice Transgenic Matrix metalloproteinase Real-Time Polymerase Chain Reaction General Biochemistry Genetics and Molecular Biology Mice Rheumatology Downregulation and upregulation Osteoarthritis Animals Humans Immunology and Allergy Medicine Cells Cultured business.industry Synovial Membrane DNA medicine.disease FHL2 Gene Expression Regulation Chronic Disease Cancer research Tumor necrosis factor alpha medicine.symptom business Signal Transduction Transcription Factors Transforming growth factor |
| Zdroj: | Annals of the rheumatic diseases, 74(12), 2216-2223. BMJ Publishing Group |
| ISSN: | 1468-2060 0003-4967 |
| Popis: | ObjectiveWe analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 & Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease.MethodsSynovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined. Analyses of human tissue specimens from patients treated with anti-TNFα as well as anti-TNFα treatment of hTNFtg mice were performed to substantiate the TNFα effects on FHL2 levels. FHL2−/− mice and hTNFtg mice (with constitutive or inducible transgene expression) were crossbred to generate TNFα overexpressing FHL2-deficient animals. Signalling pathways were analysed in cells from these mice and in human cells after knock down of FHL2 by western blot.ResultsFHL2 levels were higher in RA than in OA and in hTNFtg than in wild-type mice. Surprisingly, while transforming growth factor (TGF)β-induced FHL2 expression, TNFα suppressed FHL2. In vivo, anti-TNFα treatment led to higher FHL2 levels both in RA patients and hTNFtg mice. The loss of FHL2 increased joint destruction in hTNFtg mice, which was accompanied by elevated MMP-13. In vitro, TNFα-mediated MMP-13 was significantly higher in FHL2−/− cells and after knock down of FHL2, which was caused by prolonged p38 MAPK activation.ConclusionsThese data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt. |
| Databáze: | OpenAIRE |
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