RESUMO
Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes. Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood. Leukocyte mobilization by A485 was equally potent as, but mechanistically distinct from, granulocyte colony-stimulating factor (G-CSF), which allowed for additive neutrophil mobilization when both compounds were combined. These effects were maintained in models of leukopenia and conferred augmented host defenses. Mechanistically, activation of the hypothalamus-pituitary-adrenal gland (HPA) axis by A485 relayed shifts in leukocyte distribution through corticotropin-releasing hormone receptor 1 (CRHR1) and adrenocorticotropic hormone (ACTH), but independently of glucocorticoids. Our findings identify a strategy for rapid expansion of the blood leukocyte compartment via a neuroendocrine loop, with implications for the treatment of human pathologies.
Assuntos
Medula Óssea , Histona Acetiltransferases , Humanos , Histona Acetiltransferases/metabolismo , Medula Óssea/metabolismo , Histonas/metabolismo , Neutrófilos/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismoRESUMO
Periodontitis is associated with significant alveolar bone loss. Patients with iron overload suffer more frequently from periodontitis, however, the underlying mechanisms remain largely elusive. Here, we investigated the role of transferrin receptor 2 (Tfr2), one of the main regulators of iron homeostasis, in the pathogenesis of periodontitis and the dental phenotype under basal conditions in mice. As Tfr2 suppresses osteoclastogenesis, we hypothesized that deficiency of Tfr2 may exacerbate periodontitis-induced bone loss. Mice lacking Tfr2 (Tfr2-/- ) and wild-type (Tfr2+/+ ) littermates were challenged with experimental periodontitis. Mandibles and maxillae were collected for microcomputed tomography and histology analyses. Osteoclast cultures from Tfr2+/+ and Tfr2-/- mice were established and analyzed for differentiation efficiency, by performing messenger RNA expression and protein signaling pathways. After 8 days, Tfr2-deficient mice revealed a more severe course of periodontitis paralleled by higher immune cell infiltration and a higher histological inflammation index than Tfr2+/+ mice. Moreover, Tfr2-deficient mice lost more alveolar bone compared to Tfr2+/+ littermates, an effect that was only partially iron-dependent. Histological analysis revealed a higher number of osteoclasts in the alveolar bone of Tfr2-deficient mice. In line, Tfr2-deficient osteoclastic differentiation ex vivo was faster and more efficient as reflected by a higher number of osteoclasts, a higher expression of osteoclast markers, and an increased resorptive activity. Mechanistically, Tfr2-deficient osteoclasts showed a higher p38-MAPK signaling and inhibition of p38-MAPK signaling in Tfr2-deficient cells reverted osteoclast formation to Tfr2+/+ levels. Taken together, our data indicate that Tfr2 modulates the inflammatory response in periodontitis thereby mitigating effects on alveolar bone loss.
Assuntos
Perda do Osso Alveolar , Periodontite , Animais , Humanos , Camundongos , Perda do Osso Alveolar/genética , Perda do Osso Alveolar/metabolismo , Ferro , Osteoclastos , Periodontite/genética , Periodontite/metabolismo , Receptores da Transferrina/genética , Microtomografia por Raio-X , Camundongos Endogâmicos C57BL , Células CultivadasRESUMO
Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4-2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to - 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4-2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4-2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4-2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.
Assuntos
Acil Coenzima A , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias da Próstata , Masculino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1 , Sinvastatina/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Caspases , DipiridamolRESUMO
Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.
Assuntos
Perda do Osso Alveolar/imunologia , Proteínas de Transporte/metabolismo , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Periodontite/metabolismo , Envelhecimento/imunologia , Animais , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/imunologia , Proteínas de Transporte/farmacologia , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Integrinas/antagonistas & inibidores , Integrinas/imunologia , Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-17/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Atrofia Periodontal/imunologia , Atrofia Periodontal/metabolismo , Periodontite/imunologia , Periodontite/terapia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/metabolismoRESUMO
BACKGROUND: Leucine-rich α-2 glycoprotein 1 (LRG-1) is a secreted glycoprotein that is mainly produced in the liver. Elevated levels of LRG-1 are found in a multitude of pathological conditions including eye diseases, diabetes, infections, autoimmune diseases, and cancer. In patients with early breast cancer (BC), high intratumoral LRG-1 protein expression levels are associated with reduced survival. In this study, we assessed serum levels of LRG-1 in patients with early BC and investigated its correlation with the presence of disseminated tumor cells (DTCs) in the bone marrow and survival outcomes. METHODS: Serum LRG-1 levels of 509 BC patients were determined using ELISA and DTCs were assessed by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. We stratified LRG-1 levels according to selected clinical parameters. Using the log-rank (Mantel-Cox) test and multivariate Cox regression analysis, Kaplan-Meier survival curves and prognostic relevance were assessed. RESULTS: Mean serum levels of LRG-1 were 29.70 ± 8.67 µg/ml. Age was positively correlated with LRG-1 expression (r = 0.19; p < 0.0001) and significantly higher LRG-1 levels were found in patients over 60 years compared to younger ones (30.49 ± 8.63 µg/ml vs. 28.85 ± 8.63 µg/ml; p = 0.011) and in postmenopausal patients compared to premenopausal patients (30.15 ± 8.34 µg/ml vs. 26.936.94 µg/ml; p = 0.002). Patients with no DTCs showed significantly elevated LRG-1 levels compared to the DTC-positive group (30.51 ± 8.69 µg/ml vs. 28.51 ± 8.54 µg/ml; p = 0.004). Overall and BC-specific survival was significantly lower in patients with high serum LRG-1 levels (above a cut-off of 33.63 µg/ml) compared to patients with lower LRG-1 levels during a mean follow-up of 8.5 years (24.8% vs. 11.1% BC-specific death; p = 0.0003; odds ratio 2.63, 95%CI: 1.56-4.36). Multivariate analyses revealed that LRG-1 is an independent prognostic marker for BC-specific survival (p = 0.001; hazard ratio 2.61). CONCLUSIONS: This study highlights the potential of LRG-1 as an independent prognostic biomarker in patients with early BC.
Assuntos
Neoplasias da Mama , Glicoproteínas , Humanos , Feminino , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Pessoa de Meia-Idade , Glicoproteínas/sangue , Idoso , Adulto , Biomarcadores Tumorais/sangue , Prognóstico , Estimativa de Kaplan-Meier , Idoso de 80 Anos ou mais , Modelos de Riscos ProporcionaisRESUMO
Thyroid hormones (TH) are important modulators of bone remodeling and thus, thyroid diseases, in particular hyperthyroidism, are able to compromise bone quality and fracture resistance. TH actions on bone are mediated by the thyroid hormone receptors (TR) TRα1 and TRß1, encoded by Thra and Thrb, respectively. Skeletal phenotypes of mice lacking Thra (Thra0/0 ) and Thrb (Thrb-/- ) are well-described and suggest that TRα1 is the predominant mediator of TH actions in bone. Considering that bone cells might be affected by systemic TH changes seen in these mutant mice, here we investigated the effects of TR knockout on osteoblasts exclusively at the cellular level. Primary osteoblasts obtained from Thra0/0 , Thrb-/- , and respective wildtype (WT) mice were analyzed regarding their differentiation potential, activity and TH responsiveness in vitro. Thra, but not Thrb knockout promoted differentiation and activity of early, mature and late osteoblasts as compared to respective WT cells. Interestingly, while mineralization capacity and expression of osteoblast marker genes and TH target gene Klf9 was increased by TH in WT and Thra-deficient osteoblasts, Thrb knockout mitigated the responsiveness of osteoblasts to short (48 h) and long term (10 d) TH treatment. Further, we found a low ratio of Rankl, a potent osteoclast stimulator, over osteoprotegerin, an osteoclast inhibitor, in Thrb-deficient osteoblasts and in line, supernatants obtained from Thrb-/- osteoblasts reduced numbers of primary osteoclasts in vitro. In accordance to the increased Rankl/Opg ratio in TH-treated WT osteoblasts only, supernatants from these cells, but not from TH-treated Thrb-/- osteoblasts increased the expression of Trap and Ctsk in osteoclasts, suggesting that osteoclasts are indirectly stimulated by TH via TRß1 in osteoblasts. In conclusion, our study shows that both Thra and Thrb differentially affect activity, differentiation and TH response of osteoblasts in vitro and emphasizes the importance of TRß1 to mediate TH actions in bone.
Assuntos
Receptores dos Hormônios Tireóideos , Receptores alfa dos Hormônios Tireóideos , Camundongos , Animais , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Receptores beta dos Hormônios Tireóideos/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Biologia , Ligante RANK/metabolismo , Camundongos KnockoutRESUMO
Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.
Assuntos
Glucocorticoides , Receptores Adrenérgicos beta , Masculino , Animais , Camundongos , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Receptores Adrenérgicos beta/metabolismo , Corticosterona/metabolismo , Seguimentos , Camundongos Endogâmicos C57BL , Tecido Adiposo/metabolismo , Obesidade/induzido quimicamente , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Lipídeos , TermogêneseRESUMO
Clonal hematopoiesis (CH) is an age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of healthy hematopoietic cells in experimental hematology. We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease who were undergoing THA. Prevalence of CH was 50%, including 77 patients with CH of indeterminate potential (CHIP, defined as somatic variant allele frequencies [VAFs] ≥2%), and 23 patients harboring CH with lower mutation burden (VAF, 1% to 2%). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%), and ASXL1 (3.5%). CHIP is significantly associated with lower hemoglobin, higher mean corpuscular volume, previous or present malignant disease, and CVD. Strikingly, we observed a previously unreported association of CHIP with autoimmune diseases (AIDs; multivariable adjusted odds ratio, 6.6; 95% confidence interval, 1.7-30; P = .0081). These findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for managing patients with OA and AIDs or mild anemia and question the use of hip bone-derived cells as healthy experimental controls.
Assuntos
Artroplastia de Quadril , Doenças Autoimunes/genética , Hematopoiese Clonal , Frequência do Gene , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/complicações , Células Cultivadas , DNA Metiltransferase 3A/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE OF REVIEW: Osteoclasts are crucial for the dynamic remodeling of bone as they resorb old and damaged bone, making space for new bone. Metabolic reprogramming in these cells not only supports phenotypic changes, but also provides the necessary energy for their highly energy-consuming activity, bone resorption. In this review, we highlight recent developments in our understanding of the metabolic adaptations that influence osteoclast behavior and the overall remodeling of bone tissue. RECENT FINDINGS: Osteoclasts undergo metabolic reprogramming to meet the energy demands during their transition from precursor cells to fully mature bone-resorbing osteoclasts. Recent research has made considerable progress in pinpointing crucial metabolic adaptations and checkpoint proteins in this process. Notably, glucose metabolism, mitochondrial biogenesis, and oxidative respiration were identified as essential pathways involved in osteoclast differentiation, cytoskeletal organization, and resorptive activity. Furthermore, the interaction between these pathways and amino acid and lipid metabolism adds to the complexity of the process. These interconnected processes can function as diverse fuel sources or have independent regulatory effects, significantly influencing osteoclast function. Energy metabolism in osteoclasts involves various substrates and pathways to meet the energetic requirements of osteoclasts throughout their maturation stages. This understanding of osteoclast biology may provide valuable insights for modulating osteoclast activity during the pathogenesis of bone-related disorders and may pave the way for the development of innovative therapeutic strategies.
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Reabsorção Óssea , Osteoclastos , Humanos , Osteoclastos/metabolismo , Metabolismo Energético , Reabsorção Óssea/metabolismo , Osso e Ossos/metabolismo , Diferenciação CelularRESUMO
OBJECTIVES: This study aimed to spatiotemporally analyze the profile of influenza-like illness (ILI) outbreaks in the state of São Paulo, Brazil, between 2020 and 2022. STUDY DESIGN: This was a cross-sectional retrospective study. METHODS: Outbreaks of ILI with final diagnoses of COVID-19, influenza, or other respiratory viruses (ORVs) recorded between January 2020 and November 2022, obtained from the Notifiable Diseases Information System (SINAN NET) Outbreak module, were analyzed. Kernel density estimates and Getis-Ord Gi∗ statistics were performed to identify spatial clusters. RESULTS: A total of 13,314 ILI outbreaks were identified, involving 130,568 cases and 2649 deaths. Of these, 104,399 (80%) were confirmed as COVID-19, 15,861 (12%) were confirmed as ORV, and 10,308 (8%) were confirmed as influenza. The year 2021 had the highest number of outbreaks and cases. Schools recorded the most outbreaks and cases, followed by long-term care facilities for older adults (LTCs). The highest average number of cases per outbreak and the highest attack rates occurred at social gatherings and prisons. Prisoners were three times more likely to contract COVID-19 during outbreaks than people in other institutions. The highest hospitalization and mortality rates for all virus types occurred in the LTC group. The occurrence and intensity of outbreaks were highly heterogeneous among the different institutions after the introduction of new SARS-CoV-2 variants in the state. CONCLUSIONS: ILI outbreaks were not randomly distributed; they clustered in specific areas. Transmissibility varied among different institutions with different responses to the COVID-19 pandemic. These results can be used as a basis for prioritizing actions and allocating resources during future pandemics.
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COVID-19 , Influenza Humana , Viroses , Humanos , Idoso , COVID-19/epidemiologia , Influenza Humana/epidemiologia , Pandemias , SARS-CoV-2 , Estudos Retrospectivos , Estudos Transversais , Brasil/epidemiologia , Surtos de DoençasRESUMO
OBJECTIVES: In 2020, Brazil experienced two concurrent public health challenges related to respiratory disease: wildfires and increased mortality due to the coronavirus (COVID-19) pandemic. Smoke from these wildfires contributed to a variety of air pollutants, including fine particulate matter (PM2.5). The present study aims to investigate the effects of environmental and socio-economic factors on COVID-19 hospitalisation in the Pantanal. STUDY DESIGN: Ecological retrospective study. METHODS: We applied a multilevel negative binomial model to relate monthly hospitalisation data with environmental variables. RESULTS: We showed that monthly PM2.5 concentration levels had the greatest influence on the increase in hospitalisations by COVID-19 in the elderly (23 % increase). The Gini index, a coefficient that reflects income inequalities, also had a positive association with COVID-19 hospitalisations (18 % increase). Higher temperatures and humidity were protective factors, showing a 15 % and 14 % decrease in hospitalisations, respectively. The results of the present study suggest that high PM2.5 exposure contributed to the increase in COVID-19 hospitalisations, as did the social inequalities of each municipality. CONCLUSIONS: The present study highlights the importance of gathering evidence supported by multiple information sources to guide decision-making and identify populations needing better public health systems.
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COVID-19 , Incêndios Florestais , Humanos , Idoso , Fumaça/efeitos adversos , Áreas Alagadas , Estudos Retrospectivos , Brasil/epidemiologia , COVID-19/epidemiologia , Material Particulado/análiseRESUMO
In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. INTRODUCTION: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. METHODS: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. RESULTS: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. CONCLUSIONS: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Fraturas por Osteoporose , Humanos , Feminino , Denosumab/efeitos adversos , Método Duplo-Cego , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Fraturas por Osteoporose/induzido quimicamente , Osteoporose Pós-Menopausa/complicaçõesRESUMO
The use of standard procedures for the diagnosis of osteoporosis and assessment of fracture risk significantly decreased during the COVID-19 pandemic, while the incidence of fragility fractures was mostly unaltered. Both COVID-19 per se and its treatments are associated with a negative impact on bone health. Preclinical models show that mice infected with SARS-CoV2 even without symptoms display loss of trabecular bone mass two weeks post infection, due to increased numbers of osteoclasts. Osteoporosis medications do not aggravate the clinical course of COVID-19, while preclinical data suggests possible beneficial effects of some therapies. While vitamin D deficiency is clearly associated with a worse clinical course of COVID-19, evidence of improved patient outcome with vitamin D supplementation is lacking. Osteoporosis treatment should not be generally discontinued, and recommendations for substituting therapies are available. Osteoporosis therapies do not interfere with the efficacy or side-effect profiles of COVID-19 vaccines and should not be stopped or indefinitely delayed because of vaccination.
Assuntos
COVID-19 , Fraturas Ósseas , Osteoporose , Animais , Vacinas contra COVID-19 , Fraturas Ósseas/complicações , Humanos , Camundongos , Osteoporose/tratamento farmacológico , Pandemias , RNA Viral/uso terapêutico , SARS-CoV-2 , Vitamina D/uso terapêuticoRESUMO
OBJECTIVES: Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown. METHODS: sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria). RESULTS: Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01-12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46-13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73-11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320-0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004). CONCLUSIONS: This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.
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Neoplasias Ovarianas , Neoplasias Peritoneais , Ascite , Biomarcadores Tumorais , Antígeno Ca-125 , Carcinoma Epitelial do Ovário , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Ovarianas/metabolismo , PrognósticoRESUMO
PURPOSE OF REVIEW: The incidence of diabetes is increasing worldwide. Diabetes mellitus is characterized by hyperglycemia, which in the long-term damages the function of many organs including the eyes, the vasculature, the nervous system, and the kidneys, thereby imposing an important cause of morbidity for affected individuals. More recently, increased bone fragility was also noted in patients with diabetes. While patients with type 1 diabetes mellitus (T1DM) have low bone mass and a 6-fold risk for hip fractures, patients with type 2 diabetes mellitus (T2DM) have an increased bone mass, yet still display a 2-fold elevated risk for hip fractures. Although the underlying mechanisms are just beginning to be unraveled, it is clear that diagnostic tools are lacking to identify patients at risk for fracture, especially in the case of T2DM, in which classical tools to diagnose osteoporosis such as dual X-ray absorptiometry have limitations. Thus, new biomarkers are urgently needed to help identify patients with diabetes who are at risk to fracture. RECENT FINDINGS: Previously, microRNAs have received great attention not only for being involved in the pathogenesis of various chronic diseases, including osteoporosis, but also for their value as biomarkers. Here, we summarize the current knowledge on microRNAs and their role in diabetic bone disease and highlight recent studies on miRNAs as biomarkers to predict bone fragility in T1DM and T2DM. Finally, we discuss future directions and challenges for their use as prognostic markers.
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Doenças Ósseas , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Fraturas do Quadril , MicroRNAs , Osteoporose , Biomarcadores , Densidade Óssea , Doenças Ósseas/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/epidemiologia , Fraturas do Quadril/epidemiologia , Humanos , Osteoporose/epidemiologiaRESUMO
Bone in diabetes mellitus is characterized by an altered microarchitecture caused by abnormal metabolism of bone cells. Together with diabetic neuropathy, this is associated with serious complications including impaired bone healing culminating in complicated fractures and dislocations, especially in the lower extremities, so-called Charcot neuroarthropathy (CN). The underlying mechanisms are not yet fully understood, and treatment of CN is challenging. Several in vitro and in vivo investigations have suggested positive effects on bone regeneration by modifying biomaterials with sulfated glycosaminoglycans (sGAG). Recent findings described a beneficial effect of sGAG for bone healing in diabetic animal models compared to healthy animals. We therefore aimed at studying the effects of low- and high-sulfated hyaluronan derivatives on osteoclast markers as well as gene expression patterns of osteoclasts and osteoblasts from patients with diabetic CN compared to non-diabetic patients with arthritis at the foot and ankle. Exposure to sulfated hyaluronan (sHA) derivatives reduced the exaggerated calcium phosphate resorption as well as the expression of genes associated with bone resorption in both groups, but more pronounced in patients with CN. Moreover, sHA derivatives reduced the release of pro-inflammatory cytokines in osteoclasts of patients with CN. The effects of sHA on osteoblasts differed only marginally between patients with CN and non-diabetic patients with arthritis. These results suggest balancing effects of sHA on osteoclastic bone resorption parameters in diabetes.
Assuntos
Artropatia Neurogênica , Reabsorção Óssea , Diabetes Mellitus , Pé Diabético , Neuropatias Diabéticas , Osteoartrite , Animais , Artropatia Neurogênica/etiologia , Artropatia Neurogênica/complicações , Ácido Hialurônico/farmacologia , Sulfatos/farmacologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/complicações , Glicosaminoglicanos , Reabsorção Óssea/complicações , Osteoartrite/complicações , Pé Diabético/complicaçõesRESUMO
Bone fragility is an adverse outcome of type 2 diabetes mellitus (T2DM). The underlying molecular mechanisms have, however, remained largely unknown. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression in health and disease states. The aim of this study was to investigate the genome-wide regulation of miRNAs in T2DM bone disease by analyzing serum and bone tissue samples from a well-established rat model of T2DM, the Zucker Diabetic Fatty (ZDF) model. We performed small RNA-sequencing analysis to detect dysregulated miRNAs in the serum and ulna bone of the ZDF model under placebo and also under anti-sclerostin, PTH, and insulin treatments. The dysregulated circulating miRNAs were investigated for their cell-type enrichment to identify putative donor cells and were used to construct gene target networks. Our results show that unique sets of miRNAs are dysregulated in the serum (n = 12, FDR < 0.2) and bone tissue (n = 34, FDR < 0.2) of ZDF rats. Insulin treatment was found to induce a strong dysregulation of circulating miRNAs which are mainly involved in metabolism, thereby restoring seven circulating miRNAs in the ZDF model to normal levels. The effects of anti-sclerostin treatment on serum miRNA levels were weaker, but affected miRNAs were shown to be enriched in bone tissue. PTH treatment did not produce any effect on circulating or bone miRNAs in the ZDF rats. Altogether, this study provides the first comprehensive insights into the dysregulation of bone and serum miRNAs in the context of T2DM and the effect of insulin, PTH, and anti-sclerostin treatments on circulating miRNAs.
Assuntos
Diabetes Mellitus Tipo 2 , MicroRNAs , Animais , Osso e Ossos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina , Ratos , Ratos ZuckerRESUMO
Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (-37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.
Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Osteoblastos/fisiologia , Neoplasias da Próstata/genética , Animais , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Comunicação Celular , Linhagem Celular Tumoral , Proliferação de Células , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Exossomos/genética , Vesículas Extracelulares/metabolismo , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Osteogênese , Transcriptoma/genética , Microambiente TumoralRESUMO
The regulation of motor resonance processes in daily life is indispensable. The automatic imitation task is an experimental model of those daily-life motor resonance processes. Recent research suggests that both self-other distinction and cognitive control processes may be involved in interference control during automatic imitation. Yet, we lack a clear understanding of the chronological sequence of interacting processes. To this end, this study used event-related potentials (ERPs) to investigate the time course underlying interference control during automatic imitation. We moreover aimed to extend previous results by investigating its modulation by social context. Cognitive conflict/action monitoring was assessed with the N2, in an exploratory manner the N450, and the CRN components. The Pre-Motor Positivity (PMP), associated with movement initiation, was suggested as a possible correlate of the successful resolution of self-other distinction. The cognitive control/action monitoring ERP components were influenced by the social context manipulation and partly by congruency, while PMP amplitudes were only sensitive to congruency. In addition, the exploratorily investigated N450 component predicted response times on incongruent relative to congruent trials in the different social contexts. This suggested that cognitive control/action monitoring processes, reflected in the N450, are guiding behavioral outcomes. Overall, interference control may primarily be guided by processes of cognitive control/action monitoring, whilst being modulated by social context demands.
Assuntos
Eletroencefalografia , Comportamento Imitativo , Cognição , Potenciais Evocados , Humanos , Tempo de ReaçãoRESUMO
The bone microenvironment is a complex tissue in which heterogeneous cell populations of hematopoietic and mesenchymal origin interact with environmental cues to maintain tissue integrity. Both cellular and matrix components are subject to physiologic challenges and can dynamically respond by modifying cell/matrix interactions. When either component is impaired, the physiologic balance is lost. Here, we review the current state of knowledge of how glycosaminoglycans - organic components of the bone extracellular matrix - influence the bone micromilieu. We point out how they interact with mediators of distinct signaling pathways such as the RANKL/OPG axis, BMP and WNT signaling, and affect the activity of bone remodeling cells within the endosteal niche summarizing their potential for therapeutic intervention.