@article{DotterweichSchlegelmilchKelleretal.2016, author = {Dotterweich, Julia and Schlegelmilch, Katrin and Keller, Alexander and Geyer, Beate and Schneider, Doris and Zeck, Sabine and Tower, Robert J. J. and Ebert, Regina and Jakob, Franz and Sch{\"u}tze, Norbert}, title = {Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells-implications for myeloma bone disease}, series = {Bone}, volume = {93}, journal = {Bone}, doi = {10.1016/j.bone.2016.08.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186688}, pages = {155-166}, year = {2016}, abstract = {Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.}, language = {en} } @article{DotterweichTowerBrandletal.2016, author = {Dotterweich, Julia and Tower, Robert J. and Brandl, Andreas and M{\"u}ller, Marc and Hofbauer, Lorenz C. and Beilhack, Andreas and Ebert, Regina and Gl{\"u}er, Claus C. and Tiwari, Sanjay and Sch{\"u}tze, Norbert and Jakob, Franz}, title = {The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease}, series = {PLoS One}, volume = {11}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0155087}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146960}, pages = {e0155087}, year = {2016}, abstract = {Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.}, language = {en} } @article{SeefriedMuellerDeubertSchwarzetal.2010, author = {Seefried, Lothar and Mueller-Deubert, Sigrid and Schwarz, Thomas and Lind, Thomas and Mentrup, Birgit and Kober, Melanie and Docheva, Denitsa and Liedert, Astrid and Kassem, Moustapha and Ignatius, Anita and Schieker, Matthias and Claes, Lutz and Wilke, Winfried and Jakob, Franz and Ebert, Regina}, title = {A small scale cell culture system to analyze mechanobiology using reporter gene constructs and polyurethane dishes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68099}, year = {2010}, abstract = {Mechanical forces are translated into biochemical signals and contribute to cell differentiation and phenotype maintenance. Mesenchymal stem cells and their tissuespecific offspring, as osteoblasts and chondrocytes, cells of cardiovascular tissues and lung cells are sensitive to mechanical loading but molecules and mechanisms involved have to be unraveled. It is well established that cellular mechanotransduction is mediated e.g. by activation of the transcription factor SP1 and by kinase signaling cascades resulting in the activation of the AP1 complex. To investigate cellular mechanisms involved in mechanotransduction and to analyze substances, which modulate cellular mechanosensitivity reporter gene constructs, which can be transfected into cells of interest might be helpful. Suitable small-scale bioreactor systems and mechanosensitive reporter gene constructs are lacking. To analyze the molecular mechanisms of mechanotransduction and its crosstalk with biochemically induced signal transduction, AP1 and SP1 luciferase reporter gene constructs were cloned and transfected into various cell lines and primary cells. A newly developed bioreactor and small-scale 24-well polyurethane dishes were used to apply cyclic stretching to the transfected cells. 1 Hz cyclic stretching for 30 min in this system resulted in a significant stimulation of AP1 and SP1 mediated luciferase activity compared to unstimulated cells. In summary we describe a small-scale cell culture/bioreactor system capable of analyzing subcellular crosstalk mechanisms in mechanotransduction, mechanosensitivity of primary cells and of screening the activity of putative mechanosensitizers as new targets, e.g. for the treatment of bone loss caused by both disuse and signal transduction related alterations of mechanotransduction.}, subject = {Bioreaktor}, language = {en} } @article{SteinertKunzPrageretal.2015, author = {Steinert, Andre F. and Kunz, Manuela and Prager, Patrick and G{\"o}bel, Sascha and Klein-Hitpass, Ludger and Ebert, Regina and N{\"o}th, Ulrich and Jakob, Franz and Gohlke, Frank}, title = {Characterization of bursa subacromialis-derived mesenchymal stem cells}, series = {Stem Cell Research \& Therapy}, volume = {6}, journal = {Stem Cell Research \& Therapy}, number = {114}, doi = {10.1186/s13287-015-0104-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126446}, year = {2015}, abstract = {Introduction The bursa subacromialis (BS) provides the gliding mechanism of the shoulder and regenerates itself after surgical removal. Therefore, we explored the presence of mesenchymal stem cells (MSCs) within the human adult BS tissue and characterized the BS cells compared to MSCs from bone marrow (BMSCs) on a molecular level. Methods BS cells were isolated by collagenase digest from BS tissues derived from patients with degenerative rotator cuff tears, and BMSCs were recovered by adherent culture from bone-marrow of patients with osteoarthritis of the hip. BS cells and BMSCs were compared upon their potential to proliferate and differentiate along chondrogenic, osteogenic and adipogenic lineages under specific culture conditions. Expression profiles of markers associated with mesenchymal phenotypes were comparatively evaluated by flow cytometry, immunohistochemistry, and whole genome array analyses. Results BS cells and BMSCs appeared mainly fibroblastic and revealed almost similar surface antigen expression profiles, which was \(CD44^+, CD73^+, CD90^+, CD105^+, CD106^+\),\(STRO-1^+, CD14^-, CD31^-, CD34^- , CD45^-, CD144^-\). Array analyses revealed 1969 genes upregulated and 1184 genes downregulated in BS cells vs. BMSCs, indicating a high level of transcriptome similarity. After 3 weeks of differentiation culture, BS cells and BMSCs showed a similar strong chondrogenic, adipogenic and osteogenic potential, as shown by histological, immunohistochemical and RT-PCR analyses in contrast to the respective negative controls. Conclusions Our in vitro characterizations show that BS cells fulfill all characteristics of mesenchymal stem cells, and therefore merit further attention for the development of improved therapies for various shoulder pathologies.}, language = {en} } @article{EbertJakobMeissnerWeigletal.2014, author = {Ebert, Regina and Jakob, Franz and Meissner-Weigl, Jutta and Zeck, Sabine and M{\"a}{\"a}tt{\"a}, Jorma and Auriola, Seppo and de Sousa, Sofia Coimbra and Mentrup, Birgit and Graser, Stephanie and Rachner, Tilman D. and Hofbauer, Lorenz C.}, title = {Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells}, doi = {10.1186/1476-4598-13-265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111174}, year = {2014}, abstract = {Background: Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/ pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects μM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. Methods: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. Results: Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. Conclusions: In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid- and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members good candidates as BP modulators. Further studies will have to unravel if treatment with such BP-sensitizers translates into preclinical and clinical efficacy.}, language = {en} } @article{JakobEbertRudertetal.2012, author = {Jakob, Franz and Ebert, Regina and Rudert, Maximilian and N{\"o}th, Ulrich and Walles, Heike and Docheva, Denitsa and Schieker, Matthias and Meinel, Lorenz and Groll, J{\"u}rgen}, title = {In situ guided tissue regeneration in musculoskeletal diseases and aging}, series = {Cell and Tissue Research}, volume = {347}, journal = {Cell and Tissue Research}, number = {3}, doi = {10.1007/s00441-011-1237-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124738}, pages = {725-735}, year = {2012}, abstract = {In situ guided tissue regeneration, also addressed as in situ tissue engineering or endogenous regeneration, has a great potential for population-wide "minimal invasive" applications. During the last two decades, tissue engineering has been developed with remarkable in vitro and preclinical success but still the number of applications in clinical routine is extremely small. Moreover, the vision of population-wide applications of ex vivo tissue engineered constructs based on cells, growth and differentiation factors and scaffolds, must probably be deemed unrealistic for economic and regulation-related issues. Hence, the progress made in this respect will be mostly applicable to a fraction of post-traumatic or post-surgery situations such as big tissue defects due to tumor manifestation. Minimally invasive procedures would probably qualify for a broader application and ideally would only require off the shelf standardized products without cells. Such products should mimic the microenvironment of regenerating tissues and make use of the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. This is especially important because the main target populations for such applications are the elderly and diseased. The quality of regenerative cells is impaired in such organisms and high levels of inhibitors also interfere with regeneration and healing. In metabolic bone diseases like osteoporosis, it is already known that antagonists for inhibitors such as activin and sclerostin enhance bone formation. Implementing such strategies into applications for in situ guided tissue regeneration should greatly enhance the efficacy of tailored procedures in the future.}, language = {en} } @article{KlotzMentrupRegensburgeretal.2012, author = {Klotz, Barbara and Mentrup, Birgit and Regensburger, Martina and Zeck, Sabine and Schneidereit, Jutta and Schupp, Nicole and Linden, Christian and Merz, Cornelia and Ebert, Regina and Jakob, Franz}, title = {1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity}, series = {PLoS ONE}, volume = {7}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0029959}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133392}, pages = {e29959}, year = {2012}, abstract = {1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence-and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.}, language = {en} } @article{LiedertRoentgenSchinkeetal.2014, author = {Liedert, Astrid and R{\"o}ntgen, Viktoria and Schinke, Thorsten and Benisch, Peggy and Ebert, Regina and Jakob, Franz and Klein-Hitpass, Ludger and Lennerz, Jochen K. and Amling, Michael and Ignatius, Anita}, title = {Osteoblast-Specific Krm2 Overexpression and Lrp5 Deficiency Have Different Effects on Fracture Healing in Mice}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {7}, issn = {1932-6203}, doi = {10.1371/journal.pone.0103250}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115782}, pages = {e103250}, year = {2014}, abstract = {The canonical Wnt/beta-catenin pathway plays a key role in the regulation of bone remodeling in mice and humans. Two transmembrane proteins that are involved in decreasing the activity of this pathway by binding to extracellular antagonists, such as Dickkopf 1 (Dkk1), are the low-density lipoprotein receptor related protein 5 (Lrp5) and Kremen 2 (Krm2). Lrp 5 deficiency (Lrp5(-/-)) as well as osteoblast-specific overexpression of Krm2 in mice (Col1a1-Krm2) result in severe osteoporosis occurring at young age. In this study, we analyzed the influence of Lrp5 deficiency and osteoblast-specific overexpression of Krm2 on fracture healing in mice using flexible and semi-rigid fracture fixation. We demonstrated that fracture healing was highly impaired in both mouse genotypes, but that impairment was more severe in Col1a1-Krm2 than in Lrp5(-/-) mice and particularly evident in mice in which the more flexible fixation was used. Bone formation was more reduced in Col1a1-Krm2 than in Lrp5(-/-) mice, whereas osteoclast number was similarly increased in both genotypes in comparison with wild-type mice. Using microarray analysis we identified reduced expression of genes mainly involved in osteogenesis that seemed to be responsible for the observed stronger impairment of healing in Col1a1-Krm2 mice. In line with these findings, we detected decreased expression of sphingomyelin phosphodiesterase 3 (Smpd3) and less active beta-catenin in the calli of Col1a1-Krm2 mice. Since Krm2 seems to play a significant role in regulating bone formation during fracture healing, antagonizing KRM2 might be a therapeutic option to improve fracture healing under compromised conditions, such as osteoporosis.}, language = {en} } @article{EbertDotterweichKrausetal.2014, author = {Ebert, Regina and Dotterweich, Julia and Kraus, Sabrina and Tower, Robert J. and Jakob, Franz and Sch{\"u}tze, Norbert}, title = {Mesenchymal stem cell contact promotes CCN1 splicing and transcription in myeloma cells}, doi = {10.1186/1478-811X-12-36}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110497}, year = {2014}, abstract = {CCN family member 1 (CCN1), also known as cysteine-rich angiogenic inducer 61 (CYR61), belongs to the extracellular matrix-associated CCN protein family. The diverse functions of these proteins include regulation of cell migration, adhesion, proliferation, differentiation and survival/apoptosis, induction of angiogenesis and cellular senescence. Their functions are partly overlapping, largely non-redundant, cell-type specific, and depend on the local microenvironment. To elucidate the role of CCN1 in the crosstalk between stromal cells and myeloma cells, we performed co-culture experiments with primary mesenchymal stem cells (MSC) and the interleukin-6 (IL-6)-dependent myeloma cell line INA-6. Here we show that INA-6 cells display increased transcription and induction of splicing of intron-retaining CCN1 pre-mRNA when cultured in contact with MSC. Protein analyses confirmed that INA-6 cells co-cultured with MSC show increased levels of CCN1 protein consistent with the existence of a pre-mature stop codon in intron 1 that abolishes translation of unspliced mRNA. Addition of recombinant CCN1-Fc protein to INA-6 cells was also found to induce splicing of CCN1 pre-mRNA in a concentration-dependent manner. Only full length CCN1-Fc was able to induce mRNA splicing of all introns, whereas truncated recombinant isoforms lacking domain 4 failed to induce intron splicing. Blocking RGD-dependent integrins on INA-6 cells resulted in an inhibition of these splicing events. These findings expand knowledge on splicing of the proangiogenic, matricellular factor CCN1 in the tumor microenvironment. We propose that contact with MSC-derived CCN1 leads to splicing and enhanced transcription of CCN1 which further contributes to the translation of angiogenic factor CCN1 in myeloma cells, supporting tumor viability and myeloma bone disease.}, language = {en} } @phdthesis{EbertDuemig2000, author = {Ebert-D{\"u}mig, Regina}, title = {Expression und Regulation 1,25(OH) 2 -Vitamin D 3-responsiver Gene in monozyt{\"a}ren Zellen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-1101}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2000}, abstract = {Das Secosterid Vitamin D3 wird durch die Nahrung aufgenommen oder im Organismus synthetisiert, wobei eine Reaktion in der Haut durch einen photochemischen Prozess katalysiert wird.Durch zwei Hydroxylierungsschritte in Leber und Niere wird Vitamin D3 {\"u}ber 25(OH) Vitamin D3 zum aktiven 1,25(OH)2 Vitamin D3-Hormon. 1,25(OH)2 Vitamin D3 hat eine wichtige Funktion im Knochenstoffwechsel, es reguliert die Ca2+-Resorption im D{\"u}nndarm. Die 1,25(OH)2 Vitamin D3-Synthese in der Niere wird durch Parathormon (PTH) kontrolliert. Ist die Serum Ca2+-Konzentration niedrig, wird PTH ausgesch{\"u}ttet und die 1a-Hydroxylase, das 25(OH) Vitamin D3-aktivierende Enzym, stimuliert. Das Prinzip der (Seco)steroid-Aktivierung und -Inaktivierung in glandul{\"a}ren Organen, wie Leber und Niere mit anschließender Freisetzung der aktiven Hormone und Transport zu den jeweiligen Zielgeweben gilt heute nicht mehr uneingeschr{\"a}nkt. Auch Einzelzellen sind in der Lage Steroid-modifizierende Enzyme, die Hydroxylasen und Dehydrogenasen, zu exprimieren. Monozyt{\"a}re Zellen exprimieren das 1,25(OH)2 Vitamin D3-aktivierende und das -inaktivierende Enzym, die 1a-Hydroxylase und die 24-Hydroxylase. Sie sind somit in der Lage, 1,25(OH)2 Vitamin D3 zu sezernieren, welches parakrin auf Nachbarzellen wirken kann. In diesem Zusammenhang wurde die Expression und Regulation der 1a-Hydroxylase in peripheren Blutmonozyten (PBM) und monozyt{\"a}ren THP1-Zellen untersucht. Durch Supplementation der Zellen mit dem Substrat 25(OH) Vitamin D3 konnte die Produktion an aktivem 1,25(OH)2 Vitamin D3-Hormon in PBM signifikant gesteigert werden. In PBM konnte im Gegensatz zum systemischen Ca2+-Stoffwechsel nur ein geringer Einfluss auf die 1a-Hydroxylase-Aktivit{\"a}t beobachtet werden. Durch RT-PCR-Amplifikation konnte eine Expression des PTH Rezeptors Typ 1 (PTHR1) in PBM und Dendritischen Zellen nachgewiesen werden. Ein weiterer Ligand des PTHR1 ist PTH related Protein (PTHrP), ein Faktor der die Tumorhyperkalz{\"a}mie propagiert. Durch Markierungsexperimente mit fluoreszenz-markiertem PTHrP konnte gezeigt werden, dass PTHrP an die Zellmembran von PBM und Dendritischen Zellen bindet und in den Zellkern von Dendritischen Zellen transportiert wird. Im Rahmen dieser Arbeit wurde die Expression 1,25(OH)2 Vitamin D3-responsive Gene in Monozyten/Makrophagen untersucht. Die Expression der 24-Hydroxylase wird innerhalb der Differenzierung von myeloischen THP1-Zellen zu Makrophagen- bzw. Osteoklasten-{\"a}hnlichen Zellen transient induziert. Als weiteres 1,25(OH)2 Vitamin D3-responsives Gen wurde die Expression von Osteopontin (OPN) untersucht. OPN ist ein vor allem in Knochen vorkommendes Matrixprotein, das wesentlich an der Zelladh{\"a}sion beteiligt ist. OPN wird in THP1-Zellen im Zuge der Differenzierung zunehmend exprimiert. Durch immunhistochemische Untersuchungen konnte OPN in Granulomen von Morbus Crohn- und Leberschnitten detektiert werden. Es spielt hier eine wesentliche Rolle bei der Granulomentstehung. Die Thioredoxin Reduktase 1 (TR1) ist ein Selenoenzym, welches maßgeblich an der Reduktion von Disulfidbindungen in Proteinen beteiligt ist. Es moduliert Protein/Protein- und Protein/DNA-Interaktionen wie die Bindung der Transkriptionsfaktoren AP1 und NFkB an DNA-responsive Elemente. Die Expression der TR1 wird in THP1-Zellen im Rahmen der Differenzierung induziert und ist in differenzierten Zellen maximal. Aktivit{\"a}tsmessungen deckten sich mit dieser Beobachtung. In peripheren Blutmonozyten steigt die TR-Aktivit{\"a}t alleine durch Adh{\"a}sion der Zellen an das Kulturgef{\"a}ß und nach Behandlung mit 1,25(OH)2 Vitamin D3. Die Untersuchungen der vorliegenden Arbeit zeigten eine Abh{\"a}ngigkeit der TR-Aktivit{\"a}t vom Differenzierungsgrad der Zellen und der Supplementation des Mediums mit dem Spurenelement Selen. Die Expression weiterer Selenoproteine in monozyt{\"a}ren Zellen wurde nachgewiesen. So konnten durch 75Selenit-Markierungsexperimente neun Selenoproteine in THP1-Zellen detektiert werden, von denen f{\"u}nf sezerniert werden. Ein weiteres, in monozyt{\"a}ren Zellen charakterisiertes Selenoprotein ist die zellul{\"a}re Glutathionperoxidase. Ihre Aktivit{\"a}t konnte in Selenit-supplementierten Zellen um das 70fache gesteigert werden. Die Kultivierung monozyt{\"a}rer Zellen unter Selenit-Supplementation beeinflusst die Funktion dieser Zellen wesentlich. So konnte beobachtet werden, dass die Anzahl an phagozytierenden, zu Makrophagen differenzierten THP1-Zellen nach Selenit-Supplementation abnahm, w{\"a}hrend die Phagozytoserate der einzelnen Zellen anstieg. Die erzielten Ergebnisse zeigen, dass monozyt{\"a}re Zellen mit Komponenten des 1,25(OH)2 Vitamin D3 Stoffwechsels ausgestattet sind und aktives 1,25(OH)2 Vitamin D3-Hormon produzieren, sezernieren und inaktivieren k{\"o}nnen. Die lokale Kontrolle der 1,25(OH)2 Vitamin D3 Stoffwechsels ausgestattet sind und aktives 1,25(OH)2 Vitamin D3-responsiver Gene, wie die Expression des Selenoproteins TR1, das einen direkten Einfluss auf den Redoxstatus und den Abbau reaktiver Sauerstoffverbindungen in diesen und Nachbarzellen aus{\"u}bt.}, subject = {Vitamin D3}, language = {de} }