Die Rolle Sentrin spezifischer Proteasen in der stabilen Aktivierung von Synovialfibroblasten bei Patienten mit Rheumatoider Arthritis

Im Rahmen dieser Dissertation wurde die Rolle von SENP5 und 7 in der stabilen Aktivierung von Rheumatoid Arthritischen Synovialfibroblasten (RASF) untersucht. Erstmalig konnte eine erhöhte Expression von SUMO-2/3 sowie der SUMO-spezifischen Protease SENP7 in Rheumatoid Arthritischen Synovialfibroblasten und Synovialfibroblasten von hTNFtg-Mäusen nachgewiesen werden. SENP5 wurde ebenfalls im RA-Synovialgewebe detektiert. Neben der nukleären Lokalisation von SENP5/7 in RASF konnte für SENP7 auch eine zytoplasmatische Lokalisation gezeigt werden. TNF-alpha wirkte in murinen wt-SF stimulierend auf die SENP7 Expression. Die Überexpression von SENP5/7 steigerte die Proliferationsraten muriner wt und hTNFtg SF sowie die FASL-induzierte Apoptose in wt SF. Zusätzlich steigerte die Überexpression von SENP7 die FASL-induzierte Apotose in RASF und induzierte die proMMP-9 Expression in wt SF. Die hier gewonnenen Erkenntnisse zeigen erstmalig Bezüge von SENP5/7 zur Rheumatoiden Arthritis

Histone deacetylases in RA: epigenetics and epiphenomena

Reduced synovial expression of histone deacetylases (HDACs) is proposed to contribute to pathology in rheumatoid arthritis (RA) by enhancing histone-dependent access of transcription factors to promoters of inflammatory genes. In the previous issue of Arthritis Research & Therapy, Kawabata and colleagues provided independent evidence that HDAC activity is increased in the synovium and fibroblast-like synoviocytes (FLSs) of patients with RA and is paralleled by increased HDAC1 expression and synovial tumor necrosis factor-alpha (TNFα) production. Remarkably, stimulation of RA FLSs with TNFα specifically increases HDAC activity and HDAC1 expression, suggesting that changes in synovial HDAC activity and expression may be secondary to local inflammatory status

Interaction of SET domains with histones and nucleic acid structures in active chromatin

Changes in the normal program of gene expression are the basis for a number of human diseases. Epigenetic control of gene expression is programmed by chromatin modifications—the inheritable “histone code”—the major component of which is histone methylation. This chromatin methylation code of gene activity is created upon cell differentiation and is further controlled by the “SET” (methyltransferase) domain proteins which maintain this histone methylation pattern and preserve it through rounds of cell division. The molecular principles of epigenetic gene maintenance are essential for proper treatment and prevention of disorders and their complications. However, the principles of epigenetic gene programming are not resolved. Here we discuss some evidence of how the SET proteins determine the required states of target genes and maintain the required levels of their activity. We suggest that, along with other recognition pathways, SET domains can directly recognize the nucleosome and nucleic acids intermediates that are specific for active chromatin regions

PI3K{gamma} regulates cartilage damage in chronic inflammatory arthritis

The gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) has been viewed as restricted to leukocytes mediating the regulation of chemokine-induced migration and recruitment of neutrophils, monocytes, and macrophages. In line with the observation that PI3Kgamma-deficient mice display defects in adaptive immunity, inhibition of PI3Kgamma reduces synovial inflammation in the collagen-induced arthritis mouse model of inflammatory arthritis [rheumatoid arthritis (RA)], which has been attributed to reduced influx of inflammatory cells. Challenging the concept of leukocyte-restricted PI3Kgamma function, we report here a novel, nonredundant function of PI3Kgamma as an important regulator of fibroblast-induced cartilage destruction during chronic destructive arthritis. We show that in human tumor necrosis factor transgenic mice, the loss of PI3Kgamma leads to a milder inflammatory arthritis. Interestingly, PI3Kgamma deficiency does not alter the recruitment of inflammatory cells, but significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes. In vitro analyses demonstrate that the decreased invasiveness of fibroblasts is mediated by reduced phosphorylation of Akt and extracellular signal-regulated kinase. Using a PI3Kgamma specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3Kgamma. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3Kgamma is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3Kgamma will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA.-Hayer, S., Pundt, N., Peters, M. A., Wunrau, C., Kühnel, I., Neugebauer, K., Strietholt, S., Zwerina, J., Korb, A., Penninger, J., Joosten, L. A. B., Gay, S., Rückle, T., Schett, G., Pap, T. Phosphatidylinositol 3-kinase-gamma regulates cartilage damage in chronic inflammatory arthritis

Large-Scale Assessments in the Norwegian Context

This chapter provides a brief overview of national and international large-scale assessment in Norway. Embedded in a range of assessment tools that consist of mapping tests in grades 1–4, national assessments in grades 5–9, national exams at the end of lower and upper secondary school and student surveys in grades 7–11, the international large-scale assessments (ILSAs) have a specific role. This role is described, as well as the assessment system as a whole. Norwegian results from the ILSAs are presented with a focus on long-term developments since the mid-1990s and equity as the most characteristic result regarding Norway seen from an international perspective. Finally, the benefits and limitations of the assessment system in its whole, and with its different tools, are discussed against a framework that distinguishes between educational monitoring, support for teaching and learning and certification as core functions of educational assessments. Conclusions are drawn regarding the possibilities to further develop the whole assessment system and its individual tools