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Kolb D.,Medical University of Graz | Pritz E.,Medical University of Graz | Steinecker-Frohnwieser B.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases | Lohberger B.,Medical University of Graz | And 12 more authors.
PLoS ONE | Year: 2014

Chordomas are rare bone tumors, developed from the notochord and largely resistant to chemotherapy. A special feature of this tumor is the heterogeneity of its cells. By combining high pressure freezing (HPF) with electron tomography we were able to illustrate the connections within the cells, the cell-cell interface, and the mitochondria-associated endoplasmic reticulum membrane complex that appears to play a special role among the characteristics of chordoma. These lipid raft-like regions are responsible for lipid syntheses and for calcium signaling. Compared to other tumor cells, chordoma cells show a close connection of rough endoplasmic reticulum and mitochondria, which may influence the sphingolipid metabolism and calcium release. We quantified levels of ceramide and glycosylceramide species by the methyl tert-butyl ether extraction method and we assessed the intracellular calcium concentration with the ratiometric fluorescent dye Fura-2AM. Measurements of the changes in the intracellular calcium concentration revealed an increase in calcium due to the application of acetylcholine. With regard to lipid synthesis, glucosylceramide levels in the chordoma cell line were significantly higher than those in normal healthy cells. The accumulation of glycosylceramide in drug resistant cancer cells has been confirmed in many types of cancer and may also account for drug resistance in chordoma. This study aimed to provide a deep morphological description of chordoma cells, it demonstrated that HPF analysis is useful in elucidating detailed structural information. Furthermore we demonstrate how an accumulation of glycosylceramide in chordoma provides links to drug resistance and opens up the field for new research options. Copyright: © 2014 Kolb et al. Source

Kullich W.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases | Spiegel H.U.,University of Munster
Journal of Back and Musculoskeletal Rehabilitation | Year: 2013

BACKGROUND AND OBJECTIVES: Nuclear magnetic resonance (NMR) has been shown to stimulate repair processes and cartilage and to influence pain signalling. It represents an alternative therapy for patients suffering from osteoarthritis (OA). To prove the clinical success of this new therapeutical method, validated measuring parameters are important that are convincing for pain and function in a one-year-follow-up. METHODS: During the course of its application over the last 10 years, over 4,500 protocols of a one-year-follow-up have been collected to record the outcome of NMR therapy. This report reflects the outcome of NMR therapy on patients with the following degenerative rheumatic diseases: OA of the knee (n=2.770), OA of the hip (n=673), OA of the ankle joint (n=420) and chronic low back pain (n=655). Data were collected at baseline, 6-8 weeks and 6 and 12 months following NMR treatment. RESULTS: Pain was reduced significantly 6 weeks after NMR treatment in the cases of all four examined indications and stayed measurably reduced up to 6 and 12 months. The improvements in all three forms of pain (pain on load, pain on motion, pain at rest) following NMR treatment were around 21-50% on average. CONCLUSIONS: Following therapy with NMR, patients with OA of all four types experienced a distinct improvement in their ability in functional parameters. Overall, the 10 years of a one-year-survey with multicenter data gathered on the effect of NMR therapy on patients verifiably proved its efficacy amongst patients with degenerative rheumatic diseases. © 2013 - IOS Press and the authors. All rights reserved. Source

Nicola F.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases | Markus A.,Rehabilitation Center for Rheumatic Diseases | Gunther B.,University of Salzburg | Werner K.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases
Pteridines | Year: 2011

In chronic inflammatory processes like rheumatoid arthritis (RA) and cardiovascular diseases (CVD) the role of pteridines and chemokines in the immune response is of great interest. The objectives of the study were to obtain information about an involvement of specific chemokines on the inflammatory process in patients with RA and CVD with activated production of the pteridine neopterin. 113 patients with RA according to American College of Rheumatology criteria including 24.8% suffering from CVD were included in the study (23% male, 77% female). For the assessment of monocyte activation and chemotaxis as well as the proinflammatory influence of chemokines on B-cells and angiogenesis in RA, neopterin and the chemokines CCL2, CXCL13 and CX3CL1 were measured by radio- and enzyme-immunoassays in serum. Neopterin and chemokines were all found in high concentrations. Neopterin significantly correlated with all chemokines: CXCL13 (rs = 0.368; p <0.0001), CX3CL1 (rs = 0.241; p <0.02), CCL2 (rs = 231; p <0.02), demonstrating high neopterin levels in RA patients to have a strong association to the chemokine induced chemotaxis of B-cells (CXCL13) and mononuclear cells (CX3CL1, CCL2). Significantly elevated concentrations of neopterin and CXCL13 were seen in patients with RA plus CVD compared to RA without CVD (p <0.03). The high incidence of cardiovascular diseases in rheumatoid arthritis seems to be associated with enhanced mononuclear (neopterin, CCL2) and B-cell activation (CXCL13), and as a consequence increased immune system activity. Source

Steinecker-Frohnwieser B.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases | Weigl L.,Medical University of Vienna | Kullich W.,Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases | Lohberger B.,Medical University of Graz
Osteoarthritis and Cartilage | Year: 2014

Objective: To investigate the combination of mild mechanical stimuli and a disease modifying osteoarthritis drug (DMOAD) in inflammatory activated chondrocytes and to study the combination of drug and mechanical tension on the cellular level as a model for an integrated biophysical approach for osteoarthritis (OA) treatments. Methods: Interleukin-1beta (IL-1β) stimulated C28/I2 cells underwent mild mechanically treatment while cultured in the presence of the DMOAD diacerein. The pharmacological input of diacerein was evaluated by cell viability and cell proliferation measurements. Inflammation and treatment induced changes in key regulatory proteins and components of the extracellular matrix (ECM) were characterized by quantitative real-time PCR (qPCR). The effects on metalloproteinase-1 (MMP-1) activity and glycosaminoglycan (GAG) concentration in cell supernatants of treated cells were investigated. Results: C28/I2 cells demonstrated significant changes in expression of inflammatory and cartilage destructive proteins in response to IL-1β stimulation. The chondroprotective action of diacerein in mechanically stimulated cells was mediated by a decrease in interleukin-8 (IL-8), fibronectin-1 (FN-1), collagen type I (Col 1) and MMP-1 expression levels, respectively. Augmented expression of interleukin-6 receptor (IL-6R) and the fibroblast growth factor receptors (FGFRs) by diacerein was not abolished by mechanical treatment. The observed effects were accompanied by a reduced cell proliferation rate, attenuated cell viability and extenuated MMP-1 activity. Conclusion: Diacerein diversely regulates the expression of main regulatory proteins as well as components important to regenerate and set up ECM. Mechanical stimulation does not negatively influence the chondroprotective effect induced by diacerein treatment in immortalized human C28/I2 chondrocytes. © 2014 Osteoarthritis Research Society International. Source

Lohberger B.,Medical University of Graz | Leithner A.,Medical University of Graz | Stuendl N.,Medical University of Graz | Kaltenegger H.,Medical University of Graz | And 2 more authors.
BMC Cancer | Year: 2015

Background: Chondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival. Research within the field of development and expansion of new treatment options for unresectable or metastatic diseases is of particular priority. Diacerein, a symptomatic slow acting drug in osteoarthritis (SYSADOA), implicates a therapeutic benefit for the treatment of chondrosarcoma by an antitumor activity. Methods: After treatment with diacerein the growth behaviour of the cells was analyzed with the xCELLigence system and MTS assay. Cell cycle was examined using flow cytometric analysis, RT-PCR, and western blot analysis of specific checkpoint regulators. The status for phosophorylation of mitogen-activated protein kinases (MAPKs) was analyzed with a proteome profiler assay. In addition, the possible impact of diacerein on apoptosis was investigated using cleaved caspase 3 and Annexin V/PI flow cytometric analysis. Results: Diacerein decreased the cell viability and the cell proliferation in two different chondrosarcoma cell lines in a dose dependent manner. Flow cytometric analysis showed a classical G2/M arrest. mRNA and protein analysis revealed that diacerein induced a down-regulation of the cyclin B1-CDK1 complex and a reduction in CDK2 expression. Furthermore, diacerein treatment increased the phosphorylation of p38aα and p38β MAPKs, and Akt1, Akt2, and Akt 3 in SW-1353, whereas in Cal-78 the opposite effect has been demonstrated. These observations accordingly to our cell cycle flow cytometric analysis and protein expression data may explain the G2/M phase arrest. In addition, no apoptotic induction after diacerein treatment, neither in the Cal-78 nor in the SW-1353 cell line was observed. Conclusions: Our results demonstrate for the first time that the SYSADOA diacerein decreased the viability of human chondrosarcoma cells and induces G2/M cell cycle arrest by CDK1/cyclin B1 down-regulation. © 2015 Lohberger et al. Source

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