Long-term Glucocorticoid Administration Research Articles

Pamidronate-induced irreversible symptomatic hypocalcemia in a dog with hypercalcemia after glucocorticoid withdrawal: a case report

BackgroundPamidronate is used for the treatment of hypercalcemia. However, a rare but potential adverse event of pamidronate treatment is hypocalcemia. This report describes an unusual case of severe, irreversible hypocalcemia after a single injection of pamidronate for the treatment of hypercalcemia due to glucocorticoid withdrawal in a dog.Case presentationAn 11-year-old castrated male Maltese dog presented with anorexia, vomiting, and diarrhea (day 0). The patient had calcinosis cutis throughout the body, calcification of intraabdominal organs, mild azotemia, and severe hypercalcemia. The severe calcification was attributed to long-term glucocorticoid administration, which was discontinued 1 month before presentation. Fluid therapy, diuretics, calcitonin, and a single intravenous injection of pamidronate were used for the treatment of hypercalcemia. On day 14, normocalcemia was achieved, but renal failure occurred. On day 20, severe and irreversible hypocalcemia occurred, and on day 42, the patient was euthanized at the owner’s request because of worsened hypocalcemia and renal failure.ConclusionsAlthough hypocalcemia is an extremely rare adverse event of bisphosphonate treatment, bisphosphonates like pamidronate can result in potentially life-threatening conditions according to the patient’s underlying conditions. Therefore, the patient’s condition should be closely monitored and any underlying conditions should be carefully evaluated before initiating the treatment for hypercalcemia using pamidronate.

Initiation of belimumab with higher daily prednisolone is effective for rapid glucocorticoid reduction: A 96-week retrospective study.

For appropriate glucocorticoid (GC) reduction, we investigated the optimal strategy including baseline factors that could reduce GC more than 50% with 96weeks of belimumab. This is a retrospective cohort study of Kakogawa Central City hospital from 2019 to 2023. We identified SLE patients who were receiving 200mg of belimumab weekly by subcutaneous injection for 96 weeks. The background at baseline, trends in clinical indicators, and factors involved in GC reduction were statistically analyzed. Finally, univariate and multivariate logistic analyses were carried out to identify baseline factors associated ≥50% GC reduction at 96weeks. Forty-seven patients were enrolled, with a median daily prednisolone of 5mg. Almost 90% of them received concomitant immunosuppressants and/or hydroxychloroquine. Serological indices, daily GC dose, and SLEDAI-2K scores showed significant improvement in 96weeks. At baseline, a significant negative correlation has been shown between the daily dose of GC and the duration from onset or last flare, as well as C4 levels. At 96weeks, GC reduction rate and SLEDAI-2K scores were negatively correlated with duration from onset or last flare to initiation of belimumab. Mycophenolate mofetil use was significantly frequent in patients with lupus nephritis (LN), which also correlated with the frequency of past flares. In addition, LN presence was associated with higher SLEDAI-2K scores at 96weeks, and baseline SLEDAI-2K ≥10 was associated with significantly higher GC dose at 96weeks. Univariate analysis of the factor contributing to achieving ≥50% GC reduction at 96weeks has pointed shorter disease duration and higher daily GC dose at baseline as significant variables. Finally, we performed a multivariate analysis by combining above two items with age, which extracted the higher daily GC dose at baseline as a significant variable (OR (95% CI) 1.25 (1.00 to 1.56), p = .047). Our study showed that a delay in belimumab initiation led to higher SLEDAI-2K score and difficulty in achieving a 50% GC reduction at 96weeks. Since GC-related adverse events increase with long-term administration of GC though with small daily doses, we proposed here that belimumab should be started in combination with higher daily prednisolone.

Exercise Prevents Glucocorticoid-Induced Myocardial 4-Hydroxynonenal Production.

Long-term administration of glucocorticoids (GCs) increases myocardial oxidative stress. 4-Hydroxynonenal (4-HNE) protein adducts, a marker of oxidative damage, have been associated with several cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, cardiomyopathy, and ischemia-reperfusion injury. Exercise training has been shown to have a protective effect on the heart by lowering the level of oxidative stress in cardiomyocytes. Therefore, we aimed to investigate the effect of long-term dexamethasone treatment and exercise training on myocardial 4-HNE levels. Twenty-four female Wistar albino rats were assigned to sedentary control-saline treated (C, n = 8), sedentary-dexamethasone treated (D, n = 8), and exercise training-dexamethasone treated (DE, n = 8) groups. Daily dexamethasone was injected for 28days at a 1mgkg-1 dose, while C animals were injected with the same volume of saline subcutaneously. DE animals underwent an exercise training protocol of 60min/day, 5days a week, at 25m/min-1 (0% grade) for 28days. Left ventricular 4-HNE, Hsp72 levels, and pHsp25/Hsp25 ratio were determined by Western blot. The administration of dexamethasone led to a significant elevation in 4-HNE levels in the myocardium of adult rats (p < 0.05; D vs. C). The concurrent implementation of exercise training impeded this increase (p > 0.05; DE vs. C). Exercise training induced a threefold increase in myocardial Hsp72 expression (p < 0.001; DE vs. C and D) and attenuated the dexamethasone-induced increase in Hsp25 phosphorylation (p < 0.05; C vs. D) (p < 0.001; DE vs. D). Our results indicate that long-term administration of dexamethasone is associated with an increase in cardiac 4-HNE levels, which is hindered by the addition of exercise training.

Brain vitamin D3-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity.

Vitamin D3 (VD3) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of glucocorticoid (GC) therapy. The aim of the study was to reveal the relationship between VD3 status and behavioral, structural-functional and molecular changes associated with GC-induced neurotoxicity. Female Wistar rats received synthetic GC prednisolone (5 mg/kg b.w.) with or without VD3 (1000 IU/kg b.w.) for 30 days. Behavioral, histological, physiological, biochemical, molecular biological (RT-PCR, Western blotting) methods, and ELISA were used. There was no difference in open field test (OFT), while forced swim test (FST) showed an increase in immobility time and a decrease in active behavior in prednisolone-treated rats, indicative of depressive changes. GC increased the perikaryon area, enlarged the size of the nuclei, and caused a slight reduction of cell density in CA1-CA3 hippocampal sections. We established a GC-induced decrease in the long-term potentiation (LTP) in CA1-CA3 hippocampal synapses, the amplitude of high K+-stimulated exocytosis, and the rate of Ca2+-dependent fusion of synaptic vesicles with synaptic plasma membranes. These changes were accompanied by an increase in nitration and poly(ADP)-ribosylation of cerebral proteins, suggesting the development of oxidative-nitrosative stress. Prednisolone upregulated the expression and phosphorylation of NF-κB p65 subunit at Ser311, whereas downregulating IκB. GC loading depleted the circulating pool of 25OHD3 in serum and CSF, elevated VDR mRNA and protein levels but had an inhibitory effect on CYP24A1 and VDBP expression. Vitamin D3 supplementation had an antidepressant-like effect, decreasing the immobility time and stimulating active behavior. VD3 caused a decrease in the size of the perikaryon and nucleus in CA1 hippocampal area. We found a recovery in depolarization-induced fusion of synaptic vesicles and long-term synaptic plasticity after VD3 treatment. VD3 diminished the intensity of oxidative-nitrosative stress, and suppressed the NF-κB activation. Its ameliorative effect on GC-induced neuroanatomical and behavioral abnormalities was accompanied by the 25OHD3 repletion and partial restoration of the VD3-auto/paracrine system. GC-induced neurotoxicity and behavioral disturbances are associated with increased oxidative-nitrosative stress and impairments of VD3 metabolism. Thus, VD3 can be effective in preventing structural and functional abnormalities in the brain and behavior changes caused by long-term GC administration.

Identification and Validation of Potential Ferroptosis-Related Genes in Glucocorticoid-Induced Osteonecrosis of the Femoral Head

Background and Objectives. Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a serve complication of long-term administration of glucocorticoids. Previous experimental studies have shown that ferroptosis might be involved in the pathological process of GIONFH. The purpose of this study is to identify the ferroptosis-related genes and pathways of GIONFH by bioinformatics to further illustrate the mechanism of ferroptosis in SONFH through bioinformatics analysis. Materials and Methods. The GSE123568 mRNA expression profile dataset, including 30 GIONFH samples and 10 non-GIONFH samples, was downloaded from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were obtained from the FerrDb database. First, differentially expressed genes (DEGs) were identified between the serum samples from GIONFH cases and those from controls. Ferroptosis-related DEGs were obtained from the intersection of ferroptosis-related genes and DEGs. Only ferroptosis DEGs were used for all analyses. Then, we conducted a Kyoto encyclopedia of genome (KEGG) and gene ontology (GO) pathway enrichment analysis. We constructed a protein-protein interaction (PPI) network to screen out hub genes. Additionally, the expression levels of the hub genes were validated in an independent dataset GSE10311. Results. A total of 27 ferroptosis-related DEGs were obtained between the peripheral blood samples of GIONFH cases and non-GIONFH controls. Then, GO, and KEGG pathway enrichment analysis revealed that ferroptosis-related DEGs were mainly enriched in the regulation of the apoptotic process, oxidation-reduction process, and cell redox homeostasis, as well as HIF-1, TNF, FoxO signaling pathways, and osteoclast differentiation. Eight hub genes, including TLR4, PTGS2, SNCA, MAPK1, CYBB, SLC2A1, TXNIP, and MAP3K5, were identified by PPI network analysis. The expression levels of TLR4, TXNIP and MAP3K5 were further validated in the dataset GSE10311. Conclusion. A total of 27 ferroptosis-related DEGs involved in GIONFH were identified via bioinformatics analysis. TLR4, TXNIP, and MAP3K5 might serve as potential biomarkers and drug targets for GIONFH.

Is Vitamin D3 a Worthy Supplement Protecting against Secondary Infections in Dogs with Atopic Dermatitis?

Canine atopic dermatitis (CAD) is a common, chronic, inflammatory skin disease in dogs worldwide. This disease often predisposes for secondary organisms overgrowth and skin infections with pathogens, such as Staphylococcus pseudintermedius and Malassezia pachydermatis. Unfortunately, the causes of this disease in both humans and animals are not fully understood; therefore, the only possible option is a lifelong, symptomatic treatment. The management of CAD is mainly based on limiting contact with allergens and antipruritic therapy, most often with glucocorticoids and antihistamines. A serious problem in this situation is the fact, that long-term administration of glucocorticoids leads to side effects like polyuria, alopecia, increased susceptibility to infection, muscle atrophy, and many others. For this reason, great emphasis is placed on the development of replacement and supportive therapies. It is a well-documented fact that reduced concentrations of serum vitamin D3 contribute to the severity of atopic dermatitis symptoms in humans. Moreover, unlike the most commonly used therapeutic methods, of which the main goal is to ameliorate inflammation and pruritus, namely the symptoms of AD, vitamin D3 supplementation affects some underlying factors of this disease. Therefore, in this review, we summarize the current state of knowledge regarding the role of vitamin D3 in CAD, its protective effect against secondary bacterial and fungal infections, and the potential of its supplementation in dogs.

Impact of Glucocorticoids on Cardiovascular System—The Yin Yang Effect

Glucocorticoids are not only endogenous hormones but are also administered exogenously as an anti-inflammatory and immunosuppressant for their long-term beneficial and lifesaving effects. Because of their potent anti-inflammatory property and ability to curb the cytokines, they are administered as lifesaving steroids. This property is not only made use of in the cardiovascular system but also in other major organ systems and networks. There is a fine line between their use as a protective anti-inflammatory and a steroid that could cause overuse-induced complications in major organ systems including the cardiovascular system. Studies conducted in the cardiovascular system demonstrate that glucocorticoids are required for growth and development and also for offering protection against inflammatory signals. Excess or long-term glucocorticoid administration could alter cardiac metabolism and health. The endogenous dysregulated state due to excess endogenous glucocorticoid release from the adrenals as seen with Cushing's syndrome or excess exogenous glucocorticoid administration leading to Cushing's-like condition show a similar impact on the cardiovascular system. This review highlights the importance of maintaining a glucocorticoid balance whether it is endogenous and exogenous in regulating cardiovascular health.

Zebrafish models for glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis due to excessive or long-term glucocorticoid administration, disturbing the homeostasis between bone formation and bone resorption. The bone biology of zebrafish shares a high degree of similarities with mammals. In terms of molecular level, genes and signaling pathways related to skeletogenesis are also highly correlated between zebrafish and humans. Therefore, zebrafish have been utilized to develop multiple GIOP models. Taking advantage of the transparency of zebrafish larvae, their skeletal development and bone mineralization can be readily visualized through in vivo staining without invasive experimental handlings. Moreover, the feasibility of using scales or fin rays to study bone remodeling makes adult zebrafish an ideal model for GIOP research. Here, we reviewed current zebrafish models for GIOP research, focused on the tools and methods established for examining bone homeostasis. As an in vivo, convenient, and robust model, zebrafish have an advantage in performing high-throughput drug screening and could be used to investigate the action mechanisms of therapeutic drugs.

Osteoporosis in rheumatic diseases

The article presents a review of studies that have examined osteoporosis in rheumatic diseases, including rheumatoid arthritis, spondylarthritis, psoriatic arthritis, systemic connective tissue diseases, and systemic vasculitis. The review discusses the pathogenesis, diagnosis and treatment of osteoporosis in these diseases, presents the results of epidemiological studies assessing the risk factors and the prevalence of osteoporosis in rheumatic diseases. There was a high prevalence of osteoporosis and fractures in rheumatic diseases, exceeding the population, associated primarily with systemic and local inflammation, as well as with the intake of glucocorticoids. It is indicated that the existing strategies for the treatment of rheumatic diseases may partially reduce bone loss, but long-term administration of glucocorticoids, on the contrary, increase bone resorption. The review presents data on the medications for the treatment of osteoporosis and approaches to the treatment of glucocorticoid osteoporosis.

Strontium gluconate potently promotes osteoblast development and restores bone formation in glucocorticoid-induced osteoporosis rats

Glucocorticoid-induced osteoporosis (GIOP) has emerged as a challenge after long-term glucocorticoid administration during the clinical therapy of diverse diseases. Although some candidates for GIOP treatment have been explored, there is still a lack of reliable drugs for GIOP prevention. In this study, rat bone marrow stem cells (rBMSCs) were utilized to investigate the feasibility of applying strontium gluconate (GluSr), which displays mild activity, easy absorption and good biocompatibility, for GIOP prevention. Thirty-two SD rats were divided into 4 groups to explore the effects of GluSr on osteoporosis rescue in vivo. Our results suggested that GluSr markedly alleviated dexamethasone (DEX)-induced apoptosis of osteoblast precursor cells and rBMSCs and enhanced rBMSC osteogenesis differentiation in vitro. GluSr also effectively promoted osteoblast survival, inhibited osteoclast differentiation and restored bone formation in GIOP rat models. Microarray analysis of the femora from GIOP rats treated with GluSr revealed that the signalling pathways of the glucocorticoid receptor (GR), oestrogen receptor gene (ESR) and vitamin D receptor (VDR) were involved in bone restoration by GluSr. In summary, our study proved that GluSr enhanced osteoblast differentiation and suppressed osteoclast activity both in vitro and in vivo. GluSr might function as a novel strontium reagent for GIOP prevention.

Hazards of Short- and Long-term Administration of Glucocorticoids on the Periodontium in Rats: A Histological and Electron Microscopic Study

Hazards of Short- and Long-term Administration of Glucocorticoids on the Periodontium in Rats: A Histological and Electron Microscopic Study

Noncoding RNAs in Steroid-Induced Osteonecrosis of the Femoral Head.

Steroid-induced osteonecrosis of the femoral head (ONFH) is a severe orthopedic disease caused by the long-term administration of glucocorticoids. The main pathological feature of ONFH is the gradually progressive necrosis of bone cells and the bone marrow, ultimately resulting in structural changes or even complete collapse of the femoral head. However, the exact pathogenic mechanism of ONFH remains unknown. Noncoding RNAs (ncRNAs) have emerged as very powerful regulators of gene expression, functioning at both transcriptional and posttranscriptional levels in the pathogenesis of ONFH. Here, we review the current knowledge of the role of ncRNAs, including microRNAs, long noncoding RNAs, and circular RNAs, in the pathogenesis of steroid-induced ONFH. Further focus and validation of these associations can provide new insight into the pathogenic mechanisms at the molecular level to suggest targets for treatment and prevention.

Glucocorticoid Treatment Leads to Aberrant Ion and Macromolecular Transport in Regenerating Zebrafish Fins.

Long-term glucocorticoid administration in patients undergoing immunosuppressive and anti-inflammatory treatment is accompanied by impaired bone formation and increased fracture risk. Furthermore, glucocorticoid treatment can lead to impaired wound healing and altered cell metabolism. Recently, we showed that exposure of zebrafish to the glucocorticoid prednisolone during fin regeneration impacts negatively on the length, bone formation, and osteoblast function of the regenerate. The underlying cellular and molecular mechanisms of impairment, however, remain incompletely understood. In order to further elucidate the anti-regenerative effects of continued glucocorticoid exposure on fin tissues, we performed proteome profiling of fin regenerates undergoing prednisolone treatment, in addition to profiling of homeostatic fin tissue and fins undergoing undisturbed regeneration. By using LC-MS (liquid chromatography-mass spectrometry) we identified more than 6,000 proteins across all tissue samples. In agreement with previous reports, fin amputation induces changes in chromatin structure and extracellular matrix (ECM) composition within the tissue. Notably, prednisolone treatment leads to impaired expression of selected ECM components in the fin regenerate. Moreover, the function of ion transporting ATPases and other proteins involved in macromolecule and vesicular transport mechanisms of the cell appears to be altered by prednisolone treatment. In particular, acidification of membrane-enclosed organelles such as lysosomes is inhibited. Taken together, our data indicate that continued synthetic glucocorticoid exposure in zebrafish deteriorates cellular trafficking processes in the regenerating fin, which interferes with appropriate tissue restoration upon injury.

Osteoporosis as a result of the long-term administration of glucocorticoids in patients suffering from acantholytic pemphigus

Osteoporosis as a result of the long-term administration of glucocorticoids in patients suffering from acantholytic pemphigus

Effects of long-term glucocorticoid administration on cisatracurium-induced neuromuscular blockade in patients undergoing laparoscopic operation

Objective To evaluate the effects of long-term glucocorticoid administration on cisatracurium-induced neuromuscular blockade in the patients undergoing laparoscopic operation. Methods Sixty-four patients of both sexes, aged 40-64 yr, with body mass index of 18-22 kg/m2, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, scheduled for elective laparoscopic operation under general anesthesia, were assigned into 4 groups (n=16 each) according to whether or not glucocorticoid was used for a long-term period: control (non-hormone and non-laparoscopic operation) group (group C), hormone + laparoscopic operation group (group HL), non-hormone + laparoscopic operation group (group NHL) and hormone + non-laparoscopic operation group (group HNL). Midazolam 0.03 mg/kg was injected intravenously, 8% sevoflurane was inhaled by mask, and the concentration of sevoflurane was decreased by 2% every 30 s until the concentration of 4% was reached.After loss of eyelash reflex, remifentanil 2 μg/kg was injected intravenously over 1 min, and 30 s later sevoflurane inhalation was stopped.The patients were tracheally intubated and mechanically ventilated.Anesthesia was maintained with propofol and remifentanil given by target-controlled infusion.Neuromuscular blockade was monitored with accelerograph TOF-watch SX.At 20 min of pneumoperitoneum in NHL and HL groups or 20 min after intubation in C and HNL groups, cisatracurium 0.15 mg/kg was injected intravenously.The onset time, maximal degree of N-M block, clinical duration and recovery index of cisatracurium were recorded. Results Compared with group C, the onset time was significantly prolonged, the maximal degree of N-M block was decreased, the clinical duration was shortened, and the recovery index was decreased in HL and HNL groups (P 0.05). Compared with group HNL, the clinical duration was significantly prolonged, the recovery index was increased (P 0.05), and the onset time was significantly shortened, the clinical duration was prolonged, and the recovery index was increased in group NHL (P<0.05). Compared with group NHL, the onset time was significantly prolonged, the maximal degree of N-M block was decreased, the clinical duration was shortened, and the recovery index was decreased in group HL (P<0.05). Conclusion Long-term glucocorticoid administration can weaken cisatracurium-induced neuromuscular blockade in the patients undergoing laparoscopic operation. Key words: Glucocorticoids; Laparoscopes; Atracurium

Osteoporosis as a result of the long-term administration of glucocorticoids in patients suffering from acantholytic pemphigus

Goal. To study the prevalence of glucocorticoid-induced osteoporosis in patients suffering from acantholytic pemphigus and risk of osteoporosis-related fractures. Materials and methods. The study involved 26 patients including 12 patients suffering from acantholytic pemphigus. The patients underwent dual-energy X-ray absorptiometry (DXA) for calculating bone mineral density (BMD) as well as T and Z scores. To assess the ten-year probability (absolute risk) of fractures, the FRAX model was applied. Major results. Glucocorticoid-induced osteoporosis was diagnosed in 33.3% of the AP patients receiving a glucocorticoid therapy, and osteopenia was also diagnosed in 33.3% of them; an increased risk of osteoporosis-related fractures was observed in all of the patients over 40, which entails the need in early diagnostics of pathologic bone changes and prevention of complications such as osteoporosis-related fractures. Conclusion. A high share of complications (83.3%) related to systemic GCS stipulates the need in increased cooperation between dermatologists and allied specialists.

Effect of dexamethasone on mandibular bone biomechanics in rats during the growth phase as assessed by bending test and peripheral quantitative computerized tomography.

Long-term glucocorticoid administration to growing rats induces osteopenia and alterations in the biomechanical behavior of the bone. This study was performed to estimate the effects of dexamethasone (DTX), a synthetic steroid with predominant glucocorticoid activity, on the biomechanical properties of the mandible of rats during the growth phase, as assessed by bending test and peripheral quantitative computed tomographic (pQCT) analysis. The data obtained by the two methods will provide more precise information when analyzed together than separately. Female rats aged 23 d (n=7) received 500μg.kg-1 per day of DXT for 4 weeks. At the end of the treatment period, their body weight and body length were 51.3% and 20.6% lower, respectively, than controls. Hemimandible weight and area (an index of mandibular size) were 27.3% and 9.7% lower, respectively. The right hemimandible of each animal was subjected to a mechanical 3-point bending test. Significant weakening of the bone, as shown by a correlative impairment of strength and stiffness, was observed in experimental rats. Bone density and cross-sectional area were measured by pQCT. Cross-sectional, cortical and trabecular areas were reduced by 20% to 30% in the DTX group, as were other cortical parameters, including the bone density, mineral content and cross-sectional moment of inertia. The "bone strength index" (BSI, the product of the pQCT-assessed xCSMI and vCtBMD) was 56% lower in treated rats, which compares well with the 54% and 52% reduction observed in mandibular strength and stiffness determined through the bending test. Data suggest that the corticosteroid exerts a combined, negative action on bone geometry (mass and architecture) and volumetric bone mineral density of cortical bone, which would express independent effects on both cellular (material quality) and tissue (cross-sectional design) levels of biological organization of the skeleton in the species.

Long-Term Corticosterone Exposure Decreases Insulin Sensitivity and Induces Depressive-Like Behaviour in the C57BL/6NCrl Mouse

Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its association with increased prevalence of major depressive disorder on the short-term and other behavioural adaptations on the longer term.

Verification of osteoporotic vertebral fractures caused by glucocorticoids

Long-term administration of glucocorticoids leads to rapid osteoporosis, and vertebral fractures are one of its most common complications. The methods used in identification are semi-quantitative ones, based on visual assessment, and quantitative ones, which use morphometric criteria. A 79-year-old woman, who has suffered from polymyalgia rheumatica since July 2012, was treated with prednisone at a daily dose of 20 mg. Radiography of thoracic and lumbar spine verified the reduction of body height of T 12, L3 and L4 vertebrae. Densitometry findings showed a decrease in bone density at the lumbar segment of the spine and femoral neck. Dual-energy x-ray absorptiometry device was used to perform vertebral morphometry by applying Genant semi-quantitative method, which verified crush fractures of the body of T4 and L3 vertebrae, while the L2 vertebra had a biconcave shape. The spinal deformity index parameter was 8. An intense pain developed in the back after 9 months of glucocorticoids administration. The repeated radiographic findings of thoracic and lumbar spine and vertebral morphometry, which had been done by dual-energy xray absorptiometry device, revealed deterioration in the form of serial crush fractures, while fat distribution index parameter increased to 15. Dual-energy x-ray absorptiometry finding showed a decrease in T score at the femoral neck. Long-term administration of glucocorticoids is accompanied by a rapid loss of bone mass, and vertebral fractures are one of its most common consequences. Therefore, its prevention, early diagnosis and treatment are required. The combination of qualitative conventional radiography and semi-quantitative dual-energy xray absorptiometry vertebral morphometry plays an important role in identifying vertebral fractures.

Ligand-Induced Repression of the Glucocorticoid Receptor Gene Is Mediated by an NCoR1 Repression Complex Formed by Long-Range Chromatin Interactions with Intragenic Glucocorticoid Response Elements

Glucocorticoids are among the most potent and effective agents for treating inflammatory diseases and hematological cancers. However, subpopulations of patients are often resistant to steroid therapy, and determining the molecular mechanisms that contribute to glucocorticoid resistance is thus critical to addressing this clinical problem affecting patients with chronic inflammatory disorders. Since the cellular level of the glucocorticoid receptor (GR) is a critical determinant of glucocorticoid sensitivity and resistance, we investigated the molecular mechanisms mediating repression of glucocorticoid receptor gene expression. We show here that glucocorticoid-induced repression of GR gene expression is mediated by inhibition of transcription initiation. This process is orchestrated by the recruitment of agonist-bound GR to exon 6, followed by the assembly of a GR-NCoR1-histone deacetylase 3-containing repression complex at the transcriptional start site of the GR gene. A functional negative glucocorticoid response element (nGRE) in exon 6 of the GR gene and a long-range interaction occurring between this intragenic response element and the transcription start site appear to be instrumental in this repression. This autoregulatory mechanism of repression implies that the GR concentration can coordinate repression with excess ligand, regardless of the combinatorial associations of tissue-specific transcription factors. Consequently, the chronic nature of inflammatory conditions involving long-term glucocorticoid administration may lead to constitutive repression of GR gene transcription and thus to glucocorticoid resistance.