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Biomedical subjects

Frank Buttgereit

Publications and source records attributed to Frank Buttgereit.

At least 19 recordsLinked to original sources
PubMed2006

Membrane glucocorticoid receptor expression on peripheral blood mononuclear cells in patients with ankylosing spondylitis.

OBJECTIVE: To investigate the expression of membrane glucocorticoid receptors (mGCR) on peripheral blood mononuclear cells (PBMC) in patients with ankylosing spondylitis (AS). METHODS: We used high sensitivity immunofluorescence with magnetofluorescent liposomes for the detection of mGCR on PBMC from patients with AS (n = 26) and healthy controls (n = 11). RESULTS: The frequency of mGCR+ monocytes and B lymphocytes was significantly higher in patients with AS than in controls (monocytes 12.5 +/- 9.9% vs 4.8 +/- 1.4%, B lymphocytes 8.7 +/- 6.3% vs 4.4 +/- 3.6%). We did not find mGCR on T lymphocytes. The frequency of mGCR+ cells did not correlate with variables of AS disease activity [C-reactive protein, erythrocyte sedimentation rate, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI 6, or numerical rating scales]. CONCLUSION: mGCR are upregulated in monocytes and B lymphocytes of patients with AS. This upregulation does not correlate with the humoral or overall disease activity. mGCR are not present on T lymphocytes. Our findings may be related to the limited benefit of low-dose and the efficacy of high-dose (intravenous pulse or intraarticular) glucocorticoid treatment in AS. Drugs binding selectively to mGCR may be a new therapeutic option for AS.

Adult↗
PubMed2006

Glucocorticoids cause rapid dissociation of a T-cell-receptor-associated protein complex containing LCK and FYN.

Although glucocorticoid (GC)-induced nongenomic effects have been reported, the underlying mechanisms remain unexplained. We previously described that lymphocyte-specific protein tyrosine kinase (LCK) and FYN oncogene related to SRC, FGR, YES (FYN) mediate GC-induced inhibition of T-cell-receptor (TCR) signalling. Here we characterize the underlying molecular mechanism. The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. Experiments with cells transfected with GC-receptor short interfering RNA (siRNA) showed that the GC receptor is an essential component of the TCR signalling complex. Short-term GC treatment induces dissociation of this protein complex, resulting in impaired TCR signalling as a consequence of abrogated LCK/FYN activation. HSP90siRNA-transfected cells are not able to assemble this TCR-associated multiprotein complex, and accordingly HSP90siRNA treatment mimics GC effects on LCK/FYN activities. These observations support a model for nongenomic GC-induced immunosuppression on the basis of dissolution of membrane-bound GC-receptor multiprotein complexes after GC-receptor ligation.

CD4 Antigens↗
PubMed2006

Non-genomic glucocorticoid effects to provide the basis for new drug developments.

Glucocorticoids act via genomic and non-genomic actions. The genomic glucocorticoid actions are well known and new details on processes of transactivation and transrepression have been reported recently. Here we describe the current knowledge on non-genomic glucocorticoid actions and discuss why these actions are considered to be of therapeutic relevance. It is assumed that rapid non-genomic glucocorticoid effects are mediated by three different mechanisms: (1) physicochemical interactions with cellular membranes (non-specific non-genomic effects); (2) membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; and (3) cytosolic glucocorticoid receptor (cGCR)-mediated non-genomic effects. With regard to the first mechanism, we discuss here lazaroids and the novel development of drug targeting with liposomes as the carrier system for glucocorticoids. The clinical use of the latter two mechanisms is still speculative, but intriguing ideas are being discussed in this regard.

Animals↗
PubMed2006

Effects of tacrolimus, cyclosporin A and sirolimus on MG63 cells.

The reduction in bone mineral density after organ transplantation results in increased morbidity (post-transplantation bone disease) and remains an unsolved problem. A connection with the long-term application of nonglucocorticoidal immunosuppressants is the subject of controversial discussion. We hypothesized that such substances have an influence on the skeletal system on the cellular level by modulating osteoblast differentiation. Therefore, we investigated the effects of tacrolimus, cyclosporin A and sirolimus as representative substances of nonglucocorticoidal immunosuppressants on cell proliferation and expression of bone tissue-specific genes of human osteoblasts (MG63). None of the examined substances affected cell proliferation, but all influenced the gene expression pattern towards change in cell differentiation. In detail, collagen III and XII, matrix metalloproteinase 2, SMAD2, epithelial growth factor receptor, annexin V and osteonectin expression were increased by all of the examined substances. Tacrolimus, cyclosporin A and sirolimus influence intracellular signalling pathways, transmembranous receptors and bone-specific matrix synthesis. They do not have antiproliferative or toxic effects. We postulate that the shown changes of osteoblast differentiation cause post-transplantation disease.

Bone Density↗
PubMed2005

Potencies of topical glucocorticoids to mediate genomic and nongenomic effects on human peripheral blood mononuclear cells.

Several different genomic and nongenomic mechanisms are known to mediate the important anti-inflammatory and immunomodulatory effects of glucocorticoids (GC). Genomic effects are the most important while the clinical relevance of nongenomic actions is still a matter of debate. We therefore investigated whether beclometasone and clobetasol are particularly suitable for topical application because of their specific spectrum of genomic and nongenomic actions. For these purposes we compared effects on oxygen consumption as measured with a Clark electrode (nonspecific nongenomic glucocorticoid effects), on interleukin-6 synthesis by means of ELISA (genomic effects) and on apoptosis using flow cytometry (nongenomic and genomic effects) in quiescent and mitogen-stimulated PBMC. Beclometasone and clobetasol indeed had stronger effects on the oxygen consumption of quiescent and stimulated cells at lower concentrations (10(-10) and 10(-8) M) but were less potent at higher concentrations (10(-5) and 10(-4) M) in comparison with dexamethasone. Also in terms of genomic potency, topical GC were more effective than dexamethasone at 10(-10) and 10(-8) M but gave similar results at higher concentrations. The ability of all three GC to induce apoptosis was found to be concentration-dependent and similar at concentrations between 10(-8) and 10(-5) M. But, compared with 10(-4) M dexamethasone, topical GC at 10(-4) M were significantly more effective at inducing apoptosis in both PBMC and Jurkat T-cells. These results show that topical GC have different concentration--(genomic/nongenomic) effect--ratios compared with dexamethasone: besides to the well-known genomic effects there are also significant nongenomic effects of topical glucocorticoids that already at low concentrations might be more therapeutically relevant in certain clinical conditions than currently assumed.

Anti-Inflammatory Agents↗
PubMed2005

Current use of glucocorticoids in patients with rheumatoid arthritis in Germany.

OBJECTIVE: To describe the current use of glucocorticoids in German patients with rheumatoid arthritis (RA). METHODS: We analyzed clinical and patient-derived data from 10,068 outpatients with RA from the national database of the German Collaborative Arthritis Centres for the year 2001 collected by more than 80 rheumatologists in hospitals and private practices. RESULTS: Systemic glucocorticoid therapy was prescribed for 60% of all patients with RA in rheumatologic care. The proportion of patients receiving systemic glucocorticoids in addition to disease-modifying antirheumatic drug (DMARD) therapy ranged from 53% to 81% of the patients for the various DMARDs. Glucocorticoid therapy was administered more often in combination with tumor necrosis factor inhibitors (81%), cyclosporin A (80%), or leflunomide (77%) than with more traditional DMARDs such as methotrexate (63%) or sulfasalazine (55%). Regarding the prevention and treatment of osteoporosis, 63% of patients taking systemic glucocorticoids were also receiving some type of osteoporosis therapy, as opposed to only 26% of those not taking glucocorticoids. CONCLUSION: Glucocorticoids play a pivotal role in the management of RA. This is reflected in the extensive use of low-dose glucocorticoids by German rheumatologists. Even if highly effective DMARDs are prescribed, they are accompanied by glucocorticoids, at least in the initial phase. High-dose glucocorticoids are prescribed for only a small proportion of the patients. There is increasing awareness of the risk of osteoporosis in long-term glucocorticoid treatment, demonstrated by the fact that osteoporosis medication is prescribed for a large proportion of patients taking glucocorticoids.

Antirheumatic Agents↗
PubMed2005

Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn.

Glucocorticoids (GCs) are effective immunosuppressive agents and mediate well-defined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4(+) lymphocytes and a peptide array containing 1176 different kinase consensus substrates, we generated a comprehensive profile of GC-induced rapid effects on signal transduction. The results show marked early differences in phosphorylation between GC-pretreated cells and control cells, including impaired phosphorylation of p56lck/p59fyn (Lck/Fyn) consensus substrates. Immunoprecipitation and in vitro kinase assays reveal rapid GC-induced down-modulation of Lck and Fyn kinases using SAM68 (Src [pp60c-src]-associated in mitosis 68 kDa) as a substrate. Additionally, immunoprecipitation experiments revealed reduced Lck-CD4 and Fyn-CD3 associations, suggesting GC inhibited recruitment of these kinases to the T-cell receptor complex. Western blot analysis revealed reduced phosphorylation of a series of downstream signaling intermediates following GC treatment, including protein kinase B (PKB), protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Experiments with GC receptor-negative Jurkat cells and a pharmacologic GC receptor ligand (RU486) indicated that rapid inhibition of Lck and Fyn kinases is GC receptor dependent. Parallel experiments conducted following the application of GCs in healthy individuals confirmed suppression of Lck/Fyn in T cells within 1 hour in vivo. These results identify the inhibition of Lck and Fyn kinases as rapid targets of GCs, mediated via a GC receptor-dependent pathway.

CD4-Positive T-Lymphocytes↗
PubMed2005

Correlation of different bone markers with bone density in patients with rheumatic diseases on glucocorticoid therapy.

Osteoporosis is a common concomitant disease in patients with rheumatic diseases on glucocorticoid (GC) therapy. Bone status is usually evaluated by determination of bone density in combination with clinical examinations and laboratory tests. However, the strength of individual biochemical bone makers in GC-induced osteoporosis has yet to be fully clarified. For this reason, different bone markers were investigated in correlation with bone density in patients with rheumatic diseases. Approximately 238 patients (212 women, 26 men) with a rheumatic disease and under GC therapy were examined consecutively for the first time with regard to bone density (BMD) and bone markers [osteocalcin, bone-specific alkaline phosphatase (precipitation method/tandem-MP ostase), crosslinks [pyridinoline (PYD), deoxypyridinoline (DPX), N-terminal telopeptide (NTX)]]. The daily glucocorticoid dose was 10 mg prednisone equivalent (median), and the cumulative dose was 12 g prednisone equivalent (median). None of the patients had previously taken medication for osteoporosis. Osteoporosis was demonstrated in 35.3% of the patients, osteopenia in 47.5%, and a normal BMD in 17.2%. The results of tandem-MP ostase correlated with the BMD of the lumbar spine and of the femoral neck. The values for N-terminal telopeptide and pyridinoline correlated only with the bone density of the femoral neck. All results were statistically significant, although the correlation coefficients were low. After classification of the patients according to their BMD values (osteoporosis, osteopenia and normal BMD), there were significantly more patients with bone markers above the norm in the osteoporosis group and in the osteopenia group than in the group with normal bone density. All bone markers recorded behaved similarly in relation to the bone density values. The same analysis was also undertaken for the different disease groups. In these subgroups there was also a correlation between ostase/crosslinks with BMD, but the correlation coefficients were low. A general recommendation for the routine use of a specific bone marker in patients with rheumatic diseases on glucocorticoid therapy cannot be made from a cost-benefit point of view mainly because of limited predictive power (low correlation coefficients, incomplete correlation with different sites of BMD measurement).

Adult↗
PubMed2005

Developments in glucocorticoid therapy.

Recent evidence for a disease-modifying potential of low-dose glucocorticoids (GCs) in the treatment of rheumatoid arthritis has renewed the debate on the risk benefit ratio with this therapy. Two recent developments are described that might have a positive influence on these risk benefit ratios. One is the improvement in new GC compounds--designer GCs, alterations in bioactivity, and alterations in formulations. The other is a better understanding and management of the toxicity of GCs.

Animals↗
PubMed2005

Oxygen consumption and mitochondrial membrane potential indicate developmental adaptation in energy metabolism of rat cortical neurons.

Neuronal energy needs are mainly covered via mitochondrial oxidative phosphorylation. Even if the energy supply appears identical in immature and adult brain, nevertheless quantitative differences exist. The present study focuses on the adaptations in cellular energy metabolism caused by the neuronal maturation. As main parameters of oxidative phosphorylation, cellular oxygen consumption and mitochondrial membrane potential were measured in isolated rat cortical cells using a Clark-type oxygen electrode and microfluorometric techniques. In four age groups (E18-P2, P8-P12, P16-P20, > or = P28), unstimulated neurons showed a significant age-dependent increase in basal oxygen consumption (6.1 up to 10.2 nM/min/10(7) cells). The excitatory neurotransmitter glutamate induced a further, but age- and concentration-independent, elevation of oxygen consumption to a plateau > or = 14 nM/min/10(7) cells and a complete depolarization of mitochondrial membrane in neurons > or = P8. Stimulation using K+ (5-50 mM) effected a concentration- and age-dependent increase in oxygen consumption, but a similar nearby complete depolarization of mitochondrial membrane in all tested age groups. Furthermore, uncoupling mitochondrial membrane function followed by a complete depolarization of mitochondrial membrane showed a maximal oxygen consumption (14-15 nM/min/10(7) cells) only in neurons > or = P8. These data suggest that developing and adult cortical neurons cover their increased need of energy following stimulation by an efficiency improvement of mitochondrial oxidative phosphorylation. The age-independent limited capacity of mitochondrial oxidative phosphorylation, however, causes a reduction in cellular energy disposal in mature neurons and therefore may play a critical role in the increased sensitivity of adult neurons against excitotoxicity and ischaemia.

Animals↗
PubMed2005

New Glucocorticoids on the Horizon: Repress, Don't Activate!

Glucocorticoids are highly effective drugs; their immunosuppressive and antiinflammatory actions are used in the treatment of many rheumatic and other inflammatory diseases. However, their use is sometimes considerably limited by numerous adverse reactions. For this reason, great efforts have been made in recent years to develop innovative glucocorticoids or glucocorticoid receptor ligands that have improved therapeutic effect/adverse reaction ratio. We summarize the position and critically discuss the following products that are currently under development: (1) selective glucocorticoid receptor agonists (SEGRA or dissociating glucocorticoids); (2) nitrosteroids; and (3) long-circulating liposomal glucocorticoids. Finally, we describe the state of research on membrane-bound glucocorticoid receptors as possible further targets for specific glucocorticoid actions.

Journal Article↗
PubMed2005

New glucocorticoids on the horizon: repress, don't activate!

Glucocorticoids are highly effective drugs; their immunosuppressive and antiinflammatory actions are used in the treatment of many rheumatic and other inflammatory diseases. However, their use is sometimes considerably limited by numerous adverse reactions. For this reason, great efforts have been made in recent years to develop innovative glucocorticoids or glucocorticoid receptor ligands that have improved therapeutic effect/adverse reaction ratio. We summarize the position and critically discuss the following products that are currently under development: (1) selective glucocorticoid receptor agonists (SEGRA or dissociating glucocorticoids); (2) nitrosteroids; and (3) long-circulating liposomal glucocorticoids. Finally, we describe the state of research on membrane-bound glucocorticoid receptors as possible further targets for specific glucocorticoid actions.

Animals↗
PubMed2004

Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis.

Glucocorticoids mediate their therapeutic actions mostly by genomic effects via cytosolic receptors, but some effects are too rapid to be mediated by changes at the genomic level. The detailed mechanisms of these nongenomic actions are still unclear. Membrane-bound glucocorticoid receptors (mGCR) have been suggested to be involved, although their physiological existence in humans so far is hypothetical. For the first time we demonstrate the existence of mGCR on monocytes and B cells obtained from healthy blood donors using high-sensitivity immunofluorescent staining. Immunostimulation with lipopolysaccharide increases the percentage of mGCR-positive monocytes, which can be prevented by inhibiting the secretory pathway. Overexpression of the human glucocorticoid receptor alpha alone is not sufficient to enhance mGCR expression. These in vitro findings are consistent with our clinical observation that in patients with rheumatoid arthritis the frequency of mGCR positive monocytes is increased and positively correlated with disease activity. We conclude that mGCR are 1) indeed physiologically present in healthy blood donors, but remained unidentified by conventional techniques due to their small number per cell and 2) actively up-regulated and transported through the cell after immunostimulation. These receptors may reflect a feedback mechanism of the organism upon immunostimulation and/or play a role in pathogenesis.

Adolescent↗
PubMed2003

Tumoral calcinosis revisited: pathophysiology and treatment.

In two renal failure patients, tumoral calcinoses were observed as a result of secondary hyperparathyroidism. The primary conservative therapy conducted with dietetic measures and phosphate-binding medication could not prevent the progression of the massive polytopic foci. Therefore, a subtotal parathyroidectomy was performed in one case, after which a rapid complete regression of the tumours was observed, with the exception of one location where the finding remained progressive. The second patient declined surgical intervention on the parathyroid gland. Therefore, the foci were only resected, whereby local recurrences were observed. Renal failure patients with tumoral calcinosis should undergo subtotal parathyroidectomy after initial conservative therapy. In view of the high risk of recurrence, local excision is a treatment procedure to be considered in exceptional cases only.

Adult↗
PubMed2003

Nonsteroidal antiinflammatory drugs and a selective cyclooxygenase 2 inhibitor uncouple mitochondria in intact cells.

OBJECTIVE: Uncoupling of isolated mitochondria by nonsteroidal antiinflammatory drugs (NSAIDs) has been considered relevant to the development of gastrointestinal (GI) side effects. We investigated the occurrence of NSAID-induced uncoupling of mitochondria in intact cells (rat thymocytes) compared with the effects of a selective cyclooxygenase 2 (COX-2) inhibitor. METHODS: Oxygen consumption and mitochondrial membrane potential were simultaneously measured amperometrically and by distribution of radioactive tracer molecules, respectively, in the presence and absence of pharmacologically relevant concentrations of the NSAIDs indomethacin and diclofenac and the selective COX-2 inhibitor SC-236. Analysis of data by a technique related to top-down elasticity analysis permitted assessment of the influence of these compounds on individual components of cellular energy metabolism. RESULTS: Indomethacin, diclofenac, and SC-236 increased proton leak in isolated mitochondria. Both diclofenac and SC-236 significantly stimulated proton leak in intact cells and simultaneously inhibited substrate oxidation and ATP turnover. Oxygen consumption rates of isolated cells remained unchanged over a wide concentration range of the drugs, despite significant effects on subsystems of cellular energy metabolism. CONCLUSION: NSAIDs and selective COX-2 inhibitors have significant and equally directed effects on cellular energy metabolism. They both uncouple mitochondrial respiration and inhibit substrate oxidation and ATP turnover. However, the topical effect and selective COX-2 inhibition may not be sufficient to cause NSAID-like damage to the GI tract.

Animals↗