Norbert Schütze

Publications (25)49.22 Total impact

• Article: Expression and regulation of thioredoxin reductases and other selenoproteins in bone.

  Franz Jakob, Katja Becker, Ellen Paar, Regina Ebert-Duemig, Norbert Schütze
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  ABSTRACT: The expression of thioredoxin reductases and other selenoproteins in cells of the bone microenvironment may represent an important means of regulation of bone resorption and remodeling in health and disease. Selenoproteins and their substrates may influence intracellular and extracellular redox-dependent signaling, transcription factor activity, posttranslational modification of proteins, and general or compartmentalized scavenging from ROIs. However, the evaluation of their biological role in bone and their potential in terms of therapeutic approaches is just beginning.
  Methods in Enzymology 02/2002; 347:168-79. · 2.04 Impact Factor
• Article: Expression von Selenoproteinen in Monozyten und Makrophagen — Implikationen für das Immunsystem

  Regina Ebert-Dümig, Jochen Seufert, Doris Schneider, Josef Köhrle, Norbert Schütze, Franz Jakob
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  ABSTRACT: □ Monozyten differenzieren unter dem Einfluß von 1,25(OH)2 Vitamin D3 und anderen Faktoren aus myeloischen Vorläuferzellen. Koloniestimulierende Faktoren wie (Granulozyten-)Makrophagen-stimulierender Faktor (GMCSF und MCSF) propagieren die weitere Differenzierung zu Makrophagen. Die Aktivierung von Makrophagen und die Phagozytose von fremden Partikeln sind regelmä\ig begleitet von einem sogenannten „respiratory burst“, einer erhöhten Produktion von reaktiven Sauerstoffspezies (ROS), die durch den Enzymkomplex NADPH-Oxidase bewerkstelligt wird. Gleichzeitig wird eine Anzahl antioxidativer Enzyme exprimiert, um die Zelle vor den zytotoxischen Effekten der ROS zu schützen, die gegen die eingeschlossenen Mikroorganismen gerichtet sind und möglicherweise auch Genregulationen bewirken. Gut charakterisierte Selenoproteine, die in die antioxidative „Defense“-Reaktion der Zelle involviert sind, sind die selenabhängigen Glutathionperoxidasen (zytosolische [cGPx] und plasmatische [pGPx]) und die Thioredoxinreduktasen α und β (TrxRα/β). Das zytosolische Isoenzym der GPx (cGPx) und die TrxRα werden beide im Rahmen der Differenzierung durch 1,25 (OH)2 Vitamin D3 stimuliert. GPx-Isoenzyme neutralisieren H2O2. TrxR sind entweder direkt oder indirekt über ihren Kofaktor Thioredoxin in die Proteinfaltung involviert. Sie reduzieren Sulfhydrylgruppen und beeinflussen so zum Beispiel kritische Protein/Protein-Interaktionen und Protein/DNA-Interktionen; sie modulieren somit die Dimerisation und/oder die DNA-Bindung von Transkriptionsfaktoren (Glukokortikoidrezeptor und andere Steroidhormonrezeptoren, NFκB). Darüber hinaus wurde gezeigt, daß das antibiotische und zytotoxische Peptid NK-Lysin ein Substrat für die TrxRα ist (mit der Folge der Inaktivierung des Peptids), was nahelegt, daß TrxR ein protektiver Faktor für die Zelle selbst ist. Selen wird kontrolliert und spezifisch in Selenoproteine in Form von Selenozystein (Secys) eingebaut, welches in Anwesenheit einer dredimensionalen Haarnadelstruktur der 3′UTR (Secis-Element) am Codon UGA abgelesen wird, das ohne ein geeignetes Secis-Element und im Selenmangel als opales Stop-Codon fungiert. Die oben diskutierten Prozesse können also im Selenmangel alteriert sein und andererseits durch Selensupplementation moduliert werden. □ Wir haben die TrxRα als 1,25(OH)2 Vitamin D3-responsives Protein in Monozyten charakterisiert und gezeigt, daß die Aktivität der GPx und der TrxR durch Selensupplementation in vitro und ex vivo stimuliert wird. Neuere Arbeiten zeigen, daß Thioredoxin, ein wichtiges Substrat der TrxR, nach Behandlung von Zellen mit H2O2 schnell in den Zellkern wandert. Darüber hinaus ist aber wenig bekannt über die Kompartimentalisierung des „respiratory burst“ in der Zelle und die intrazelluläre Lokalisation der antioxidativen Enzyme während dieses Vorgangs. Die Makrophagenfunktion ist alteriert, wenn der „respiratory burst“ insuffizient ist, wie zum Beispiel bei der hereditären chronischen granulomatösen Erkrankung. Andererseits ist diese aber auch gestört, wenn ein Defizit an antioxidativen Enzymen besteht. Thioredoxin wurde als Wachstumsfaktor für Lymphozyten identifiziert und ist in den „Crosstalk“ zwischen Makrophagen und Lymphozyten involviert. Die Relevanz der beschriebenen und anderer noch nicht charakterisierter Selenoproteine von Monozyten bleibt näher zu charakterisieren, wie auch die der Supplementation von Selen generell in der Nahrungskette und speziell in Situationen von kritischen Infektionen und bei der Entwicklung der Autoimmunität. □ Monocytes differentiate from myeloid precursors towards the macrophage state of differentiation under the influence of 1,25-dihydroxy vitamin D3 (1,25 [OH]2 vitamin D3) and other factors and this is further propagated by colony stimulating factors (MCSF and GMCSF). Macrophage activation and phagocytosis of foreign particles are regularly accompanied by a so called “respiratory burst”, an increase in the production of reactive oxygen species (ROS), exerted by the enzyme complex NADPH oxidase. A number of antioxidant enzymes is expressed at the same time to protect the cells from the cytotoxic effects of ROS directed against engulfed microorganisms. The selenium-dependent glutathione peroxidases and thioredoxin reductases are important examples. The cytosolic GPx isoenzyme (cGPx) and thioredoxin reductase α (TrxRα) are upregulated during the process of differentiation and under the influence of 1,25 (OH)2 vitamin D3. GPx isoenzymes neutralize H2O2. TrxR reduce sulfhydryl-groups like in cysteins either directly or via their cofactor thioredoxin and thus are involved in protein folding and critical protein-protein and protein-DNA interactions, e. g. modulation of dimerization and/or DNA-binding and ligand binding of transcription factors (glucocorticoid receptor and other steroid receptors, NFκB). In addition, the antibiotic peptide NK-lysin was shown to be a substrate for TrxRα, suggesting that TrxR protects the cell itself from the cytotoxic effects of NK-lysin. Selenium is incorporated into selenocysteine (Secys) in a regulated fashion in the presence of a hairpin structure (Secis element) in the 3′UTR of selenoprotein genes. Secis elements direct the insertion of Secys at UGA codons, which function as opal stop codons in the absence of a suitable Secis element and in selenium deficiency. The above mentioned processes might therefore be altered in relative selenium deficiency or vice versa be upregulated through selenium supplementation. □ We have shown that TrxRα is a 1,25 (OH)2 vitamin D3-responsive early gene in monocytic cells and that TrxR activity as well as GPx activity in these cells can be upregulated by the addition of selenium in vitro and ex vivo. Recent work demonstrates that thioredoxin rapidly enters the cell nucleus upon treatment of cells with H2O2, but little is known about the compartimentalization of the respiratory burst and the intracellular localization of antioxidant enzymes during that process. Macrophage function is insufficient if the generation of a respiratory burst is altered like in hereditary chronic granulomatous disease on one hand, but on the other hand is as well disturbed, if there is a lack in antioxidant enzyme activity. Thioredoxin has been identified as a lymphocyte growth factor and might therefore be involved in the crosstalk between macrophages and lymphocytes. The relevance of the above mentioned and other yet undefined monocytic selenoproteins remains to be elucidated in detail as well as the relevance of selenium supplementation in nutrition in general and in situations of critical infectious disease and autoimmunity.
  04/1999; 94:29-34.
• Article: Selenoproteine im Knochen, Gastrointestinaltrakt und in der Schilddrüse des Menschen

  Franz Jakob, Hubert Mörk, Norbert Schütze, Inge Dreher, Cornelia Schmutzler, Benno Lex, Josef Köhrle
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  ABSTRACT: □Basis: Selenium is an essential trace element, which is incorporated as selenocysteine (secys) into specific proteins in a regulated fashion. In the presence of a hairpin loop structure within the 3′ untranslated region of the mRNA the opal stop codon UGA is coding for selenocysteine. Selenoprotein functions are dependent on secys incorporation. Members of the family of deiodinases as well as the family of glutathione peroxidases, selenoprotein P and thioredoxin reductase are selenoproteins. □Discussion: Bone, the intestine and the thyroid rely on antioxidant systems against potential cell and DNA damage through endogenous and environmental peroxides and reactive oxygen species (ROS) potentially promoting inflammation and tumorigenesis. Optimized cell defense through antioxidant selenoproteins requires optimal selenium supplementation of the organism. We have analyzed the expression of selenoproteins in these tissues, thus providing molecular tools to further elucidate optimal selenium supply on a cellular level. □Conclusion: Clinical intervention studies that focus on the development of disease must confirm the relevance of optimized selenium supply for the pathogenesis, prevention and therapy of metabolic bone disease as well as chronic (autoimmune) inflammation and tumorigenesis in the thyroid and intestine.
  04/1997; 92:24-26.
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  Available from: smw.ch

  Article: Effect of polyhexanide and gentamicin on human osteoblasts and endothelial cells

  W K Ly, Akif Ince, Norbert Schütze, Christian Hendrich, Franz Jakob, Jochen Eulert, Jochen F Löhr
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  ABSTRACT: 0 0 7 ; 1 3 7 : 1 3 9 – 1 4 5 · w w w. s m w. c h Questions under study: Infection of total joint replacements is painful, disabling and difficult to treat because of the increasing bacterial resistance against antibiotics. In view of this, antiseptics show limited bacterial tolerance and have a broad-spec-trum antimicrobial activity. However, the applica-tion of antiseptics to bone is insufficiently studied in literature. Therefore, we investigated the bio-compatibility of the antiseptic polyhexanide with bone related cells and asked whether supplemen-tation to bone cement is appropiate in the manage-ment of total arthroplasty infections. Methods: We performed an in vitro study with immortalised human foetal osteoblast cells (hFOB 1.19) and human endothelial cells (EAhy 926). The cultured cells were exposed to media contain-ing various concentrations of gentamicin (12.5– 800 μg/ml) and polyhexanide (0.0006–0.01%) for six hours. We measured the phase-contrast mi-croscopy images, the cell viability, cell number and the alkaline phosphatase activity as a parameter for osteogenic function. Results: The exposure of hFOB and endothe-lial cells to polyhexanide showed a severe reduc-tion of viability and cell number. Gentamicin did not have negative effects on hFOB and endothe-lial cell number and viability. The alkaline phos-phatase activity of hFOB showed a significant de-crease after exposure to polyhexanide and gentam-icin. The viability and the cell number of endothe-lial cells seem more negatively affected by poly-hexanide than the parameters of the hFOB-cells. Conclusions: The exposure of human osteo-blasts and endothelial cells to polyhexanide at concentrations with questionable antibacterial activity resulted in severe cell damage whereas exposure to high dosed gentamicin did not. These results raise questions as to the feasibility of using antiseptics in bone cement for the treatment of total arthroplasty infections. Further in vivo studies are necessary to show the in vivo relevance of these in vitro findings. Total joint replacements are very successful in the treatment of osteoarthritis since several decades. However, device-related infection is a se-rious problem in orthopaedic surgery, which can deteriorate the excellent outcome of total joint re-placements. Improved infection control measures and systemic perioperative antibiotic prophylaxis, reduced the infection rate to 0.5–2% of patients who received joint replacements [1, 2]. The man-agement of such infections includes the often per-formed two-stage exchange arthroplasty and an ac-curate debridement of the affected tissues [3, 4]. Then an antibiotic loaded bone cement spacer is placed into the joint cavity for infection treatment, for at least 6 weeks. After this period a new joint replacement is implanted provided the infection is cured before. However, the poor efficiency of an-tibiotics against commensals in biofilms is a seri-ous cause of concern. Increasingly, pathogens are resistant to antimicrobial agents; current surveil-lance reveals steadily increasing rates of resistance to oxacillin among Staphylococcus aureus and to van-comycin among Enterococcus species [5]. The recent recovery of vancomycin-resistant S. aureus indi-cates the urgency to control antimicrobial resist-ance and to develop new approaches [6]. There-fore, the application of antiseptics could be a new approach in the battle against infection because of their lower bacterial tolerance and the broad spec-trum of antimicrobial activity [7, 8]. They are orig-inally agents which prevent or inhibit the growth or action of microorganisms on several surfaces. They are used currently for preoperative anti-sepsis of the oral cavity and conjunctives [9, 10].
• Article: Characterization of mode II-wear particles and cytokine response in a human macrophage-like cell culture.

  Olaf Rolf, Bernd Baumann, Thomas Sterner, Norbert Schütze, Franz Jakob, Jochen Eulert, Christof Paul Rader
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  ABSTRACT: Informations about wear particles in metallosis (mode II wear) and their effects in vitro and in vivo are limited. The aim of this study was to characterize wear particles obtained intraoperatively and to analyse their effects on cytokine response in an established human macrophage-like cell culture model. Wear particles were obtained intraoperatively from four patients with metallosis resulting from CrCoMo/PE/TiAIV-implants (mode II wear) (3 knee, 1 hip prosthesis). After purification, particles were characterized regarding to their composition and size (particle size analyser, electron microscopy, edx-analysis, histological slices). The effects of particles on the release of cytokines (PDGF, IL-1beta, IL-8, TNF alpha) were determined in an established human macrophage-like cell culture system by ELISA-assays. The metal wear particles consisted of TiAIV with a mean size of 0.1 +/- 0.15 microm, independent of the prosthesis location. CrCoMo particles could not be detected. In the cell culture model 1456 x 10(8) particles per 1 x 10(6) macrophages released maximum amounts of TNFalpha (8-fold) and IL-8 and IL-1beta (5-fold) while the survival rate of the cells was more than 90 percent. A particle-dependent increase of PDGF-levels could not be detected. As already shown for mode I wear particles (contact between primary bearing surfaces), also mode II wear particles cause release of bone resorbing cytokines in a macrophage-like cell culture model. Because their local and systemic effects in vivo are still not completely understood, we recommend a complete removal of wear particles in cases of metallosis to avoid possible immunological reactions of the body as well as periprosthetic osteolysis.
  Biomedizinische Technik 50(1-2):25-9. · 0.86 Impact Factor