Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis
CHARLIER, Edith ; RELIC, Biserka ; Deroyer, Céline et al
in International Journal of Molecular Sciences (2016)
Abstract: Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of ... [more ▼]
Abstract: Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1 (IL-1 ), Tumor Necrosis factor- (TNF- ), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1 /HIF-2 imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression. [less ▲]Detailed reference viewed: 16 (6 ULg)
BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death.
RELIC, Biserka ; CHARLIER, Edith ; Deroyer, Céline et al
in Oncotarget (2016), 7(17), 23370-82Detailed reference viewed: 17 (2 ULg)
Dickkopf 3 (Dkk3) is increased along human hip OA chondrocytes dedifferentiation and can modulate Wnt/Β-catenin and TGFβ Alk1/Smad1/5 signaling pathways, as well as leptin production
CHARLIER, Edith ; MALAISE, Olivier ; Deroyer, Céline et al
in Osteoarthritis and Cartilage (2016), 24(Supplement 1), 182Detailed reference viewed: 24 (3 ULg)
Glucocorticoid-induced leucine zipper (GILZ) is involved in glucocorticoid-induced and mineralocorticoid-induced leptin production by osteoarthritis synovial fibroblasts.
; ; et al
in Arthritis Research & Therapy (2016), 18(1), 219
BACKGROUND: Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of ... [more ▼]
BACKGROUND: Glucocorticoid-induced leucine zipper (GILZ) is a mediator of the anti-inflammatory activities of glucocorticoids. However, GILZ deletion does not impair the anti-inflammatory activities of exogenous glucocorticoids in mice arthritis models and GILZ could also mediate some glucocorticoid-related adverse events. Osteoarthritis (OA) is a metabolic disorder that is partly attributed to adipokines such as leptin, and we previously observed that glucocorticoids induced leptin secretion in OA synovial fibroblasts. The purpose of this study was to position GILZ in OA through its involvement in the anti-inflammatory activities of glucocorticoids and/or in the metabolic pathway of leptin induction. The influences of mineralocorticoids on GILZ and leptin expression were also investigated. METHODS: Human synovial fibroblasts were isolated from OA patients during knee replacement surgery. Then, the cells were treated with a glucocorticoid (prednisolone), a mineralocorticoid (aldosterone), a glucocorticoid receptor (GR) antagonist (mifepristone), a selective glucocorticoid receptor agonist (Compound A), mineralocorticoid receptor (MR) antagonists (eplerenone and spironolactone), TNF-alpha or transforming growth factor (TGF)-beta. Cells were transfected with shRNA lentiviruses for the silencing of GILZ and GR. The leptin, IL-6, IL-8 and matrix metalloproteinase (MMP)-1 levels were measured by ELISA. Leptin, the leptin receptor (Ob-R), GR and GILZ expression levels were analyzed by western blotting and/or RT-qPCR. RESULTS: (1) The glucocorticoid prednisolone and the mineralocorticoid aldosterone induced GILZ expression dose-dependently in OA synovial fibroblasts, through GR but not MR. Similar effects on leptin and Ob-R were observed: leptin secretion and Ob-R expression were also induced by prednisolone and aldosterone through GR; (2) GILZ silencing experiments demonstrated that GILZ was involved in the glucocorticoid-induced and mineralocorticoid-induced leptin secretion and Ob-R expression in OA synovial fibroblasts; and (3) GILZ inhibition did not alter the production of pro-inflammatory cytokines by OA synovial fibroblast or the anti-inflammatory properties of glucocorticoids. CONCLUSIONS: The absence of GILZ prevents corticoid-induced leptin and Ob-R expression without affecting the anti-inflammatory properties of glucocorticoids in OA synovial fibroblasts. Mineralocorticoids also induce leptin and Ob-R expression through GILZ. [less ▲]Detailed reference viewed: 24 (4 ULg)
Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and b-catenin activation
CHARLIER, Edith ; MALAISE, Olivier ; et al
in Osteoarthritis and Cartilage (2016)
Objective: The aetiology of OA is not fully understood although several adipokines such as leptin are known mediators of disease progression. Since leptin levels were increased in synovial fluid compared ... [more ▼]
Objective: The aetiology of OA is not fully understood although several adipokines such as leptin are known mediators of disease progression. Since leptin levels were increased in synovial fluid compared to serum in OA patients, it was suggested that joint cells themselves could produce leptin. However, exact mechanisms underlying leptin production by chondrocytes are poorly understood. Nevertheless, prednisolone, although displaying powerful anti-inflammatory properties has been recently reported to be potent stimulator of leptin and its receptor in OA synovial fibroblasts. Therefore, we investigated, in vitro, spontaneous and prednisolone-induced leptin production in OA chondrocytes, focusing on transforming growth factor-b (TGFb) and Wnt/b-catenin pathways. Design: We used an in vitro dedifferentiation model, comparing human freshly isolated hip OA chondrocytes cultivated in monolayer during 1 day (type II, COL2A1 þ; type X, COL10A1 þ and type I collagen, COL1A1 ") or 14 days (COL2A1 "; COL10A1 " and COL1A1þ). Results: Leptin expression was not detected in day1 OA chondrocytes whereas day14 OA chondrocytes produced leptin, significantly increased with prednisolone. Activin receptor-like kinase 1 (ALK1)/ALK5 ratio was shifted during dedifferentiation, from high ALK5 and phospho (p)-Smad2 expression at day1 to high ALK1, endoglin and p-Smad1/5 expression at day14. Moreover, inactive glycogen synthase kinase 3 (GSK3) and active b-catenin were only found in dedifferentiated OA chondrocytes. Smad1 and b-catenin but not endoglin stable lentiviral silencing led to a significant decrease in leptin production by dedifferentiated OA chondrocytes. Conclusions: Only dedifferentiated OA chondrocytes produced leptin. Prednisolone markedly enhanced leptin production, which involved Smad1 and b-catenin activation [less ▲]Detailed reference viewed: 22 (12 ULg)
New biomarkers for primary mitral regurgitation.
Deroyer, Céline ; ; Moonen, Marie et al
in Clinical proteomics (2015), 12
BACKGROUND: Mitral regurgitation is a frequent valvular heart disease affecting around 2.5 % of the population with prevalence directly related to aging. Degeneration of mitral valve is broadly considered ... [more ▼]
BACKGROUND: Mitral regurgitation is a frequent valvular heart disease affecting around 2.5 % of the population with prevalence directly related to aging. Degeneration of mitral valve is broadly considered as a passive ongoing pathophysiological process and little is known about its physiological deregulation. The purpose of this study was to highlight new biomarkers of mitral regurgitation in order to decipher the underlying pathological mechanism as well as to allow the diagnosis and the monitoring of the disease. RESULTS: Modulation of various blood proteins expression was examined in patients suffering from different grades of mitral regurgitation (mild, moderate and severe) compared to healthy controls. To this end, several routine clinical assays and the multi analyte profile technology targeting 184 proteins were used. High-density lipoprotein, apolipoprotein-A1, haptoglobin and haptoglobin-alpha2 chain levels significantly decreased proportionally to the degree of mitral regurgitation when compared to controls. High-density lipoprotein and apolipoprotein-A1 levels were associated with effective regurgitant orifice area and regurgitant volume. Apolipoprotein-A1 was an independent predictor of severe mitral regurgitation. Moreover, with ordinal logistic regression, apolipoprotein-A1 remained the only independent factor associated with mitral regurgitation. In addition, myxomatous mitral valves were studied by immunocytochemistry. We observed an increase of LC3, the marker of autophagy, in myxomatous mitral valves compared with healthy mitral valves. CONCLUSION: These potential biomarkers of mitral regurgitation highlighted different cellular processes that could be modified in myxomatous degenerescence: reverse cholesterol transport, antioxidant properties and autophagy. [less ▲]Detailed reference viewed: 87 (18 ULg)
Comprehensive plasma profiling for the characterization of graft-versus-host disease biomarkers
; BEGUIN, Yves ; Leprince, Pierre et al
in Talanta (2014), 125
Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of hematopoietic stem cell transplantation (HSCT), limiting its application. To optimize management of aGVHD and reduce ... [more ▼]
Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of hematopoietic stem cell transplantation (HSCT), limiting its application. To optimize management of aGVHD and reduce therapy-related toxicity, early specific markers are needed. The main objective of this study was thus to uncover diagnostic biomarkers comparing plasma protein profiles of patients at the time of acute GVHD diagnosis and of patients undergoing HSCT without aGVHD. Additional analysis of samples taken 15 days before aGVHD diagnosis was also performed to evaluate the potential of the newly discovered biomarkers for early diagnosis. To extract a maximum of information from plasma samples, we used three complementary proteomic approaches, namely 2D-DIGE, SELDI-TOF-MS and 2D-LC-MSE. We identified and confirmed by means of a independent techniques, the differential expression of several proteins indicating significantly increased inflammation response and disturbance in the coagulation cascade. The variation of these proteins was already observed 15 days before GVHD diagnosis, suggesting the potential early detection of the disease before symptoms appearance. Finally, logistic regression analysis determines a composite biomarker panel comprising fibrinogen, fragment of fibrinogen beta chain, SAA, prothrombin fragments, apolipoprotein A1 and hepcidin that optimally discriminated patients with and without GVHD. The area under the receiver operating characteristic curve distinguishing these 2 groups was 0.95. [less ▲]Detailed reference viewed: 101 (34 ULg)
Proteomic study of primary mitral regurgitation. Implication of autophagy in cellular signalling.
Doctoral thesis (2014)
Primary mitral regurgitation (MR), due to valve prolapse, is one of the most frequent valvular heart diseases affecting around 2.5% of the population. Primary mitral regurgitation is becoming increasingly ... [more ▼]
Primary mitral regurgitation (MR), due to valve prolapse, is one of the most frequent valvular heart diseases affecting around 2.5% of the population. Primary mitral regurgitation is becoming increasingly more prevalent as a result of population aging. In its most severe form, it may lead to pressure overload and heart failure with poor outcomes and about 2% of sudden death. As there is no blood biomarker available in clinical laboratories for its diagnosis, observation of clinical manifestations and echocardiography measurements constitute the current management of patients. Moreover, the molecular deregulation leading to myxomatous degeneration and mitral valve prolapse remains largely unknown. In the present work, we used a targeted and a non-targeted proteomic approach in order to identify biomarkers for the diagnosis of primary mitral regurgitation. Moreover, we brought out potential biological processes altered in the pathology. We identified 7 differentially expressed proteins between patients with or without mitral regurgitation. Differential protein levels between groups indicated a decrease in the reverse cholesterol transport, a potential oxidative stress and a haemolytic state as well as impairment in cell proliferation and apoptosis. In addition, we found an increase of autophagy activity in myxomatous mitral valves compared to healthy mitral valves. In a second part of the work, we investigated the molecular regulation of the autophagy pathway. C16-ceramide treatment allowed us to induce autophagic cell death in HCT116 cells. We found that C16-ceramide induced the phosphorylation of emerin, a nuclear membrane protein, at its LEM domain. Moreover, we highlighted that this phosphorylation was required for the induction of autophagy by emerin. Moreover, we found a direct interaction between emerin and LC3, the marker of autophagosome formation. To go further in deciphering the role of emerin in the C16-ceramide autophagy pathway, we identified new binding partners through biochemical purification and mass spectrometry analysis. [less ▲]Detailed reference viewed: 17 (2 ULg)
New role for Emerin, a key inner nuclear membrane protein, as an enhancer of the autophagosome formation in the C16-ceramide autophagy pathway.
Deroyer, Céline ; ; Merville, Marie-Paule et al
in Autophagy (2014)
To date, precise roles of EMD remain poorly described. In this paper, we investigate the role of EMD in the C16-ceramide autophagy pathway. Ceramides are bioactive signalling molecules acting notably in ... [more ▼]
To date, precise roles of EMD remain poorly described. In this paper, we investigate the role of EMD in the C16-ceramide autophagy pathway. Ceramides are bioactive signalling molecules acting notably in the regulation of cell growth, differentiation or cell death. However, the mechanisms by which they mediate these pathways are not fully understood. We found that C16-ceramide induces EMD phosphorylation on its LEM domain through PRKACA. Upon ceramide treatment, phosphorylated EMD binds LC3 leading to an increase of the autophagosomes formation. These data suggest a new role of EMD as an enhancer of autophagosomes formation in the C16-ceramide autophagy pathway in colon cancer cells. [less ▲]Detailed reference viewed: 151 (36 ULg)
Identification of protein biomarkers associated with cardiac ischemia by a proteomic approach.
Fillet, Marianne ; Deroyer, Céline ; et al
in Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals (2013), 18(7), 614-24
Angina is chest pain induced by ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. People that suffer from average to severe cases of angina have an increased ... [more ▼]
Angina is chest pain induced by ischemia of the heart muscle, generally due to obstruction or spasm of the coronary arteries. People that suffer from average to severe cases of angina have an increased percentage of death before the age of 55, usually around 60%. Therefore, prevention of major complications, optimizing diagnosis, prognosis and therapeutics are of primary importance. The main objective of this study was to uncover biomarkers by comparing serum protein profiles of patients suffering from stable or unstable angina and controls. We identified by non-targeted proteomic approach and confirmed by the means of independent techniques, the differential expression of several proteins indicating significantly increased vascular inflammation response, disturbance in the lipid metabolism and in atherogenic plaques stability. [less ▲]Detailed reference viewed: 28 (9 ULg)
Identification of new emerin partners in ceramide signalling pathway
DEROYER, Céline ; ; Merville, Marie-Paule et al
Conference (2012, May 25)Detailed reference viewed: 13 (0 ULg)
Strontium ranelate increases cell viability in IL-1 beta stimulated human chondrocytes
Merville, Marie-Paule ; Deroyer, Céline ; Bruyère, Olivier et al
in Osteoporosis International (2011, March), 22(Suppl.1), 53-54384Detailed reference viewed: 45 (22 ULg)
Le ranélate de strontium augmente la viabilité de chondrocytes humains stimulés par IL-1 bêta
Merville, Marie-Paule ; Deroyer, Céline ; Bruyère, Olivier et al
in Revue du Rhumatisme (2010, November), 77(Suppl.3), 222Detailed reference viewed: 12 (3 ULg)
Assessment of high sensitive troponin T and I immunoassays in patients with acute chest
Le Goff, Caroline ; Garweg, Christophe ; et al
in Clinical Chemistry (2010, July), 56(S6), 127
Introduction: Cardiac troponin I and T are specific markers of myocardial injury that are widely used for the diagnosis of acute coronary syndrome (ACS). In acute chest pain without ST-segment elevation ... [more ▼]
Introduction: Cardiac troponin I and T are specific markers of myocardial injury that are widely used for the diagnosis of acute coronary syndrome (ACS). In acute chest pain without ST-segment elevation, they are used to differentiate unstable angina from non ST-segment elevation myocardial infarction (NSTEMI). Recently, troponin assays with higher analytical sensitivities became available to enable the detection of minor myocardial damage and identify individuals at higher risk for ACS. As a result of its high tissue-specificity, cardiac troponin T and I are cardio-specific, highly sensitive markers for myocardial damage. The aim of this study was to evaluate the new higher sensitive troponin (T and I) in patients with stable angina and acute chest pain without ST-segment elevation. Methods: Sixty subjects (mean age : 65.5± 11 years), were included: 20 healthy controls, 20 patients with stable angina, 9 with unstable angina (troponin-) and 18 patients with NSTEMI myocardial infarction (troponin+). The protocol was approved by the ethic committee of the University of Liège (Belgium). High sensitive troponin T (hsTnT) determination was realized on heparin plasma by electrochemiluminescence immunoassay on Modular E (Roche Diagnostic). Troponin I II (TnI II) is a chemiluminescent microparticle immunoassay for the quantitative determination of cardiac troponin-I in heparine plasma on the ARCHITECT i System (Abbott Diagnostic). The lower detection limit of these assays was 0.005μg/L for hsTnT and 0.01μg/L for TnI II. Stastistical analysis was performed using t test. P value <0.05 was considered significant. Results: HsTNT levels were 0.003(0.003, 0.004) [median baseline (1st, 3rd quartile)]ng/ml in controls, 0.0075 (0.00475, 0.014) ng/ml in stable angina, 0.011(0.006, 0.012) ng/ml in unstable angina and 0.3715 (0.1795, 1.00725) ng/ml in NSTEMI ACS. TnI II levels were 0 (0, 0.001) ng/ml in controls and in patients with stable angina, 0.07 (0.005, 0.014) ng/ml in unstable angina and 1.4475 (0.0407, 2.656) ng/ml in NSTEMI. HsTNT and TnI II levels were significantly increased in NSTEMI as compared to control subjects, patients with stable and unstable angina. TnI II levels were also increased in unstable angina as compared to controls. Conclusion: In our population, TnI II was more sensitive than hsTNT to detect minor myocardial damage in patients with unstable angina as compared to controls. Therefore, future studies will have to determine whether TnI II might contribute to better risk stratification and treatment strategy in this group of patients. [less ▲]Detailed reference viewed: 144 (16 ULg)
Does echocardiographic stress test induced release of hsTnT and TnI II?
Le Goff, Caroline ; ; Garweg, Christophe et al
in Clinical Chemistry (2010, July), 56(S6), 128
Background: Cardiac troponins (cTn) are considered as the best biomarkers for detection of myocardial cell injury. In this study, cTnT and cTnI were measured by new commercially available high-sensitive ... [more ▼]
Background: Cardiac troponins (cTn) are considered as the best biomarkers for detection of myocardial cell injury. In this study, cTnT and cTnI were measured by new commercially available high-sensitive methods in patients undergoing brief exercise- or pharmacologicinduced stress. Our aim was to compare cTnT and cTnI levels before and after the stress tests, in the patients with or without reversible ischemia. Materials and Methods: Fifty patients (28 men and 22 women) underwent an echographic stress test (ST) for suspected ischemic heart disease. Of these 50 patients, 28 received pharmacological ST (dobutamine injection) and 22 dynamic ST (bicycle exercise). The patients were subdivided into two groups according to the presence or absence of documented transient reversible ischemia: 14 with reversible ischemia ( mean age: 67.71±9.66 y) and 36 without ischemia ( mean age: 63.17±11.72 y). In all patients, cTnT and cTnI concentrations were measured by high sensitive methods (hsTnT, Roche Diagnostics and TnI II, Abbott Diagnostics) on heparin plasma immediately before (T0) and after ST (T1).The lower detection limit of these assays was 0.005μg/L for hsTnT and 0.01μg/L for TnI II. The protocol was approved by the ethics committee of the University of Liège (Belgium). All patients gave informed consent. All statistical analyses were performed using Medcalc version 8.1 for Windows. P value <0.05 was regarded as statistically significant. Results: There was no significant difference between hsTnT concentrations at T0 and T1, neither in the whole patient group, nor in the subgroups of subjects who received pharmacological ST or dynamic ST. The same was true for TnI II. Although there was no change in hsTnT levels during test in ischemic and in non ischemic patients, the latter tend to demonstrate higher median T0 levels (25th, 75th percentiles) than the others [0.011 (0.007, 0.029) vs 0.007 (0.0047, 0.1125) ng/ml, p=0.09]. They also showed higher median T1 levels [0.014 (0.065, 0.03) vs 0.007 (0.003, 0.0102) ng/ml, p=0.08]. Higher TnI II levels were also recorded in ischemic patients as compared to non ischemic patients at T0[ 0.014 (0.0072; 0.0265) vs 0.005 (0.003; 0.01) ng/ml, p=0.08] and T1[ 0.013 (0.0085- 0.03) vs 0.006 (0.0035-0.008) ng/ml, p=0.08]. Also, TnI II levels did not change during test in both subgroups. Conclusions: Measurement of cardiac troponins by high sensitive methods did not allow to detect significant release of biomarkers from the heart during exercise-or pharmacologic-induced ST, even in patients who demonstrated reversible myocardial ischemia. The type of test – pharmacological or dynamic - was without effect. The patients with induced transient ischemia had however higher troponin T and I levels at baseline, this difference remaining during test. [less ▲]Detailed reference viewed: 103 (9 ULg)
Etude protéomique de l'insuffisance cardiaque. Recherche et identification de biomarqueurs des maladies coronariennes.
Master's dissertation (2007)Detailed reference viewed: 23 (0 ULg)