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Heart failure with preserved ejection fraction (HFpEF) is more prevalent in post- compared to pre-menopausal women. The underlying mechanisms are not fully understood. Data in humans is confounded by age and co-morbidities. We investigated the effects of ovariectomy and estrogen replacement on the left ventricular (LV) gene expression of pro-inflammatory and pro-fibrotic factors involved in HFpEF and putative regulating miRNAs. Nine-week-old C57BL/6 female mice were subjected to ovariectomy (OVX) or SHAM operation. OVX and SHAM groups were sacrificed 1-, 6-, and 12-weeks post-surgery (T1/SHAM; T1/OVX; T6/SHAM; T6/OVX, T12/SHAM). 17ß-estradiol (E2) or vehicle (VEH) was then administered to the OVX groups for 6 weeks (T12/OVX/E2; T12/OVX/VEH). Another SHAM group was sacrificed 12-weeks post-surgery. RNA and miRNAs were extracted from the LV apex. An early 3-fold increase in the gene expression of IL-1α, IL-6, Mmp9, Mmp12, Col1α1, and Col3α1 was observed one-week post-surgery in T1/OVX vs. T1/SHAM, but not at later time points. miRNA-26a was lower in T1/OVX vs. T1/SHAM and was inversely correlated with Col1α1 and Col3α1 expression 1-week post-surgery (r = -0.79 p < 0.001; r = -0.6 p = 0.007). miRNAs-26a, 29b, and 133a were significantly higher, while Col1α1, Col3α1, IL-1α, IL-6, Tnfα, Mmp12, and FasL gene expression was significantly lower in E2- compared to vehicle-treated OVX mice. miRNA-26a was inversely correlated with Col3α1 in T12/OVX/ E2 (r = -0.56 p = 0.02). OVX triggered an early increase in the gene expression of pro-inflammatory and pro-fibrotic factors, highlighting the importance of the early phase post-cessation of ovarian function. E2 replacement therapy, even if it was not immediately initiated after OVX, reversed these unfavorable changes and upregulated cardiac miRNA-26a, previously unknown to be affected by menopausal status.
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Colágeno Tipo I , Estradiol , Regulação da Expressão Gênica , Ventrículos do Coração , MicroRNAs , Animais , Feminino , Camundongos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Ovariectomia , Regulação para Cima/efeitos dos fármacosRESUMO
Advances in the management of people with type 1 diabetes (T1D) led to longer life expectancy, but with it an aging population with age-associated conditions. While macrovascular and microvascular complications are widely recognized, bone fragility has received considerably less attention, although fractures lead to high morbidity and mortality. Hip fracture risk is up to sixfold higher in T1D than in nondiabetic controls and significantly higher than in type 2 diabetes. Hip fractures occur at a younger age, and the consequences are worse. The risk of nonvertebral fractures is also significantly increased. Altered bone quality is a major underlying mechanism. Areal BMD measured by DXA underestimates fracture risk. BMD testing is recommended in T1D patients with poor glycemic control and/or microvascular complications. Trabecular bone score is mildly reduced, and its ability to predict fractures in T1D is unknown. Bone turnover markers, particularly procollagen type 1 N-terminal propeptide, are suppressed and do not predict fracture risk in T1D. T1D-related risk factors for fractures include disease onset at age <20 years, longer disease duration, HbA1c ≥8%, hypoglycemic episodes and microvascular complications. Data regarding the efficacy of therapeutic interventions to prevent or treat skeletal fragility in T1D is scant. Adequate calcium and vitamin D intake and fall prevention are recommended. Antiosteoporosis therapies are recommended in T1D patients with previous hip or vertebral fragility fracture, more than 1 other fragility fracture, BMD T-score < -2.5 at the femoral neck or spine, and increased FRAX score. Fracture risk assessment needs to be part of the management of people with T1D.
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Densidade Óssea , Diabetes Mellitus Tipo 1 , Fraturas Ósseas , Humanos , Diabetes Mellitus Tipo 1/complicações , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Adulto , Fatores de Risco , Osteoporose/etiologia , Osteoporose/epidemiologiaRESUMO
Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = -6.22 and Z = -6.45, respectively). Compared to previously published datasets of interleukin-1ß and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.
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Neoplasias Pulmonares , Glândula Tireoide , Humanos , Animais , Camundongos , Glândula Tireoide/metabolismo , Transcriptoma , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Anticorpos/genética , Análise de Sequência de RNARESUMO
Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Glândula Tireoide/patologia , Antígeno B7-H1 , Estudos Retrospectivos , Antineoplásicos Imunológicos/efeitos adversos , Receptor de Morte Celular Programada 1RESUMO
Introduction: Sirtuin 1 (SIRT1) is a key player in aging and metabolism and regulates bone mass and architecture. Sexual dimorphism in skeletal effects of SIRT1 has been reported, with an unfavorable phenotype primarily in female mice. Methods: To investigate the mechanisms of gender differences in SIRT1 skeletal effect, we investigated femoral and vertebral cortical and cancellous bone in global Sirt1 haplo-insufficient 129/Sv mice aged 2,7,12 months lacking Sirt1 exons 5,6,7 (Sirt1+/Δ ) and their wild type (WT) counterparts. Results: In females, femoral bone mineral content, peak cortical thickness, and trabecular bone volume (BV/TV%), number and thickness were significantly lower in Sirt1+/Δ compared to WT mice. Increased femoral cortical porosity was observed in 7-month-old Sirt1+/Δ compared to WT female mice, accompanied by reduced biomechanical strength. No difference in vertebral indices was detected between Sirt1+/Δ and WT female mice. SIRT1 decreased with aging in WT female mice and was lower in vertebrae and femur in 18- and 30- versus 3-month-old 129/Sv and C57BL/6J female mice, respectively. Decreased bone estrogen receptor alpha (ERα) was observed in Sirt1+/Δ compared to WT female mice and was significantly higher in Sirt1 over-expressing C3HT101/2 murine mesenchymal stem cells. In males no difference in femoral indices was detected in Sirt1+/Δ versus WT mice, however vertebral BV/TV%, trabecular number and thickness were higher in Sirt1+/Δ vs. WT mice. No difference in androgen receptor (AR) was detected in bone in Sirt1+/Δ vs. WT male mice. Bone SIRT1 was significantly lower in male compared to female WT mice, suggesting that SIRT1 maybe more significant in female than male skeleton. Discussion: These findings demonstrate that 50% reduction in SIRT1 is sufficient to induce the hallmarks of skeletal aging namely, decreased cortical thickness and increased porosity in female mice, highlighting the role of SIRT1 as a regulator of cortical bone quantity and quality. The effects of SIRT1 in cortical bone are likely mediated in part by its regulation of ERα. The age-associated decline in bone SIRT1 positions SIRT1 as a potential therapeutic target to ameliorate age-related cortical bone deterioration in females. The crosstalk between ERα, AR and SIRT1 in the bone microenvironment remains to be further investigated.
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Osso Cortical , Receptor alfa de Estrogênio , Osteoporose , Sirtuína 1 , Animais , Feminino , Masculino , Camundongos , Osso Cortical/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Camundongos Endogâmicos C57BL , Porosidade , Sirtuína 1/genética , Osteoporose/genética , Osteoporose/metabolismoRESUMO
OBJECTIVE: Menopause is associated with visceral adiposity, hepatic steatosis and increased risk for cardiovascular disease. As estrogen replacement therapy is not suitable for all postmenopausal women, a need for alternative therapeutics and biomarkers has emerged. METHODS: 9-week-old C57BL/6 J female mice were subjected to ovariectomy (OVX) or SHAM surgery (n = 10 per group), fed a standard diet and sacrificed 6- & 12 weeks post-surgery. RESULTS: Increased weight gain, hepatic triglyceride content and changes in hepatic gene expression of Cyp17a1, Rgs16, Fitm1 as well as Il18, Rares2, Retn, Rbp4 in mesenteric visceral adipose tissue (VAT) were observed in OVX vs. SHAM. Liver RNA-sequencing 6-weeks post-surgery revealed changes in genes and microRNAs involved in fat metabolism in OVX vs. SHAM mice. Energy Homeostasis Associated gene (Enho) coding for the hepatokine adropin was significantly reduced in OVX mice livers and strongly inversely correlated with weight gain (r = -0.7 p < 0.001) and liver triglyceride content (r = -0.4, p = 0.04), with a similar trend for serum adropin. In vitro, Enho expression was tripled by 17ß-estradiol in BNL 1 ME liver cells with increased adropin in supernatant. Analysis of open-access datasets revealed increased hepatic Enho expression in estrogen treated OVX mice and estrogen dependent ERα binding to Enho. Treatment of 5-month-old OVX mice with Adropin (i.p. 450 nmol/kg/twice daily, n = 4,5 per group) for 6-weeks reversed adverse adipokine gene expression signature in VAT, with a trended increase in lean body mass and decreased liver TG content with upregulation of Rgs16. CONCLUSIONS: OVX is sufficient to induce deranged metabolism in adult female mice. Hepatic adropin is regulated by estrogen, negatively correlated with adverse OVX-induced metabolic phenotypes, which were partially reversed with adropin treatment. Adropin should be further explored as a potential therapeutic target and biomarker for menopause-related metabolic derangement.
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Estrogênios , Fígado , Animais , Estrogênios/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Triglicerídeos/metabolismo , Aumento de PesoRESUMO
OBJECTIVE: Treatment with immune-checkpoint inhibitors often results in endocrine immune-related adverse events (irAEs), affecting the pituitary, thyroid, adrenal, and parathyroid glands and pancreas. The mechanism underlying the endocrine irAEs has not been fully elucidated, and it remains unclear why endocrine organs are so commonly affected. In the present study, we evaluated immunostaining patterns of programmed death-ligand 1 (PD-L1) in normal endocrine tissues to determine whether increased expression may explain the predilection of endocrinopathies in patients treated with programmed cell death-1 inhibitors. METHODS: Normal formalin-fixed paraffin-embedded endocrine tissues (pituitary, thyroid, adrenal, pancreas, and parathyroid) were collected from our hospital's pathology tissue archive. The tissues were assessed for membranous and cytoplasmic PD-L1 immunostaining using the Dako 22C3 pharmDx assay on an automated staining platform. RESULTS: We examined 49 endocrine tissues, including 12 thyroid, 5 pancreatic, 17 adrenal, 5 parathyroid, and 10 pituitary samples. Samples with less than 1% membranous PD-L1-positive cells were considered negative, while those with more than 1% of PD-L1 membranous staining were considered positive. Immunostaining result of immune-related cells was also evaluated, considering the cytoplasmic PD-L1-positive cells with the same cutoff of 1%. None of the endocrine tissues demonstrated PD-L1 positivity higher than 1% in the relevant cells. CONCLUSION: While our results do not suggest a role of PD-L1 expression in the pathogenesis of endocrine irAEs, they may serve as a basis for future studies further investigating the mechanisms of autoimmune, inflammatory, or malignant endocrine conditions.
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Doenças do Sistema Endócrino , Neoplasias , Antígeno B7-H1 , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/epidemiologia , Humanos , Inibidores de Checkpoint Imunológico , Incidência , Neoplasias/tratamento farmacológicoRESUMO
INTRODUCTION: Accelerated bone loss and osteoporosis are multifactorial comorbidities related to HIV and its treatments; however, their mechanisms remain elusive. Identifying HIV treatments that are differentially linked to osteoporosis risk, and clinical factors associated with HIV-related osteoporosis may enable optimizing anti-retroviral treatment (ART) and anti-osteoporosis therapy in preventing or treating this debilitating complication. This study aims to evaluate the dynamics of bone turnover markers after initiation of two commonly used antiretroviral regimens. METHODS: A prospective matched cohort study. Thirty treatment-naïve male patients (mean age 40 ± 10y) who initiated treatment with truvada (tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)) + raltegravir or TDF/FTC + efavirenz were included in the study. Control group included 15 treatment-naive HIV patients. Serum morning fasting level of P1NP and CTX were measured 0, 1, 6, and 12 months after treatment initiation in the two study groups, and at 0, 6 and 12 months in the control group. RESULTS: In both treatment groups, but not in the control group, both markers increased significantly over time with no difference in BTM between patients treated with raltegravir or efavirenz. Levels of P1NP were statistically higher at 6 and 12 months after treatment initiation in both treatment groups compared to the controls, while CTX during treatment increased in both treatment groups but was significantly higher only in the raltegravir treatment group after 12 months. The ratio of area under the curve of P1NP/CTX correlated with CD4 increment. CONCLUSIONS: Treatment initiation with raltegravir or efavirenz combined with TDF/FTC is associated with increased bone turnover. Thus, therapy that optimize bone turnover is needed to reduce bone loss at this vulnerable period and improve long-term bone health.
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CONTEXT: Obesity is a proinflammatory metabolic state that may play a role in the development of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor therapy. OBJECTIVE: To characterize the association between body mass index (BMI) and thyroid irAEs. METHODS: We performed a single-center, retrospective analysis of 185 cancer patients treated with anti-PD-1/L1 from January 2014 to December 2018. Patients with normal thyroid function at baseline and available BMI were included. MAIN OUTCOME MEASURES: The primary endpoint was difference in BMI in patients who developed overt thyroid dysfunction versus those who remained euthyroid following anti-PD-1/L1 initiation. Additional endpoints included any (overt or subclinical) thyroid dysfunction, overt thyrotoxicosis or overt hypothyroidism, and time to development of dysfunction according to BMI. RESULTS: Any thyroid dysfunction developed in 72 (38.9%) patients and 41 (22.1%) developed overt thyroid dysfunction. Mean BMI was higher in those with overt thyroid dysfunction versus euthyroid (27.3â ±â 6.0 vs 24.9â ±â 4.5, Pâ =â .03). Development of overt thyrotoxicosis versus remaining euthyroid was associated with higher BMI (28.9â ±â 5.9 vs 24.9â ±â 4.5; Pâ <â .01), whereas overt hypothyroidism was not (26.7â ±â 5.5 vs 24.9â ±â 4.5, Pâ =â .10). Overt thyrotoxicosis developed within 57.5 (interquartile range [IQR] 31.8-78.8) days of treatment in the low-normal BMI group, 38.0 (IQR 26.8-40.5) days in the overweight group, and 23.0 (IQR 21.0-28.0) days in the obese group (Pâ =â .02). CONCLUSIONS: Patients treated with PD-1/L1 inhibitors were more likely to develop thyroid irAEs, specifically overt thyrotoxicosis, with increasing BMI. Overt thyrotoxicosis occurred earlier in obese versus leaner patients. These data highlight the complex interplay between obesity and immune response in immune checkpoint inhibitor-treated patients.
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Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Obesidade/complicações , Tireotoxicose/epidemiologia , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/imunologia , Obesidade/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Fatores de Risco , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Tireotoxicose/induzido quimicamente , Tireotoxicose/imunologiaRESUMO
Objective: To characterize anti-programmed cell death 1 (PD-1)-induced thyroid immune-related adverse events (irAEs) in metastatic melanoma patients treated at our institution and to identify risk factors associated with their development. Methods: We reviewed the files of 154 patients with metastatic melanoma treated with PD-1 inhibitors at a single institution from November 1, 2011, to February 28, 2017. The association of thyroid irAEs within 120 days posttreatment initiation with age, gender, melanoma characteristics, treatment protocol, and baseline thyroid-stimulating hormone (TSH) was examined. Results: Overall, 42.4% developed thyroid dysfunction following treatment, including 20.2% (20/99) subclinical thyroid dysfunction, 13.1% (13/99) overt hypothyroidism, and 9.1% (9/99) overt hyperthyroidism. Of those that developed overt hyperthyroidism, 8 progressed to overt hypothyroidism, consistent with thyroiditis. Age, gender, melanoma characteristics, or treatment protocol did not modify the risk of developing thyroid irAEs. Higher baseline TSH was observed in patients who developed overt hypothyroidism versus hyperthyroidism versus those who remained euthyroid (P = .05). A pretreatment TSH >2.19 mIU/mL was associated with an increased risk of overt thyroid dysfunction (odds ratio, 3.46; 95% confidence interval, 1.2 to 9.8). Conclusion: Thyroid dysfunction following treatment with PD-1 inhibitors is common, and patients with a higher baseline TSH appear to be at increased risk. Such patients may benefit from closer monitoring of their thyroid function following initiation of anti PD-1 agents. Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; FT3 = free triiodothyronine; FT4 = free thyroxine; irAE = immune-related adverse event; PD-1 = programmed cell death 1; TFT = thyroid function test; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.
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Hipotireoidismo , Humanos , Receptor de Morte Celular Programada 1 , Fatores de Risco , Testes de Função Tireóidea , Tireotropina , TiroxinaRESUMO
Bone marrow adipose tissue (MAT) is influenced by nutritional cues, and participates in whole body energy metabolism. To investigate the role of Sirtuin1 (Sirt1), a key player in metabolism, in MAT, marrow adiposity was evaluated in inbred 5-month-old 129/Sv Sirt1 haplo-insufficient (Sirt1 Δ/+) and wild type (WT) mice. Decreased expression of the thermogenic genes: Prdm16, Pgc1α, Foxc2, Dio2, and ß3AR was detected in whole tibiae derived from Sirt1 Δ/+ compared to WT female mice. Similarly, decreased expression of Prdm16 and Pgc1α was observed in primary bone marrow mesenchymal stem cell (BM-MSC) cultures obtained from Sirt1 Δ/+ compared to WT female mice, suggesting a cell autonomous effect of Sirt1 in BM-MSCs. In vitro, Sirt1 over-expression in the mesenchymal embryonic fibroblast stem cell line C3HT101/2 increased Pgc1α and Prdm16 protein level. Similarly, pharmacologic activation of Sirt1 by SRT3025 increased Foxc2, Pgc1α, Dio2, Tfam, and Cyc1 expression while inhibition of Sirt1 by EX527 down-regulated UCP1 in C3HT101/2 cells. Importantly, in human femoral BM-MSCs obtained from female patients undergoing hip operations for fracture or osteoarthritis, Sirt1 activation by SRT3025 increased PGC1α mRNA and protein level. Blocking sclerostin, an inhibitor of the WNT pathway and a Sirt1 target, by the monoclonal humanized antibody (Sc-AbII), stimulated ß3AR, PRDM16, and UCP1 gene expression, and increased PGC1α protein level. These results show that Sirt1 stimulates a thermogenic gene program in marrow adipocytes in mice and humans via PGC1α activation and sclerostin inhibition. The implications of these findings to bone health, hematopoiesis and whole body energy metabolism remain to be investigated.
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One of the major clinical manifestations of familial dysautonomia (FD)-a rare, neurodegenerative, autosomal-recessive disorder-is a high incidence and early onset of osteoporotic bone fractures. Early diagnosis is essential to initiate preventative therapy in at-risk patients and thus improve quality of life. However, the current lack of understanding of the complex relationship between FD and osteoporosis etiology precludes early diagnosis, and as such, accurate predictors of osteoporosis development in FD patients remain to be determined. It has been previously reported that a restriction fragment length polymorphism in the gene encoding the vitamin D receptor (VDR) and the number of thymine-adenine (TA) repeats in the gene encoding the estrogen receptor alpha (ESR1) may each be associated with determinants of bone mineral density and may thus predict the development of osteoporosis across a number of non-FD populations. In this study, we aimed to examine the correlation between osteoporosis and the presence of these genetic polymorphisms and to establish whether they could be used as predictive markers of osteoporosis development in the context of FD. The correlations between osteoporosis and either the BsmI restriction site polymorphism in VDR or the (TA)n repeat polymorphism in ESR1 were analyzed in 73 and 67 genotyped patients, respectively. Osteoporosis was defined as a bone mineral density greater than 2.5 (T-score) or greater than 2 (Z-score) standard deviations below the mean, as measured by dual-energy X-ray absorptiometry of the spine or hip. In both instances, no statistically significant difference in the frequency of polymorphism could be detected between FD patients with and without osteoporosis. Neither polymorphism can serve as a predictive marker for the development of osteoporosis in FD patients.
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Disautonomia Familiar/genética , Receptor alfa de Estrogênio/genética , Osteoporose/genética , Polimorfismo de Fragmento de Restrição , Receptores de Calcitriol/genética , Adolescente , Adulto , Alelos , Densidade Óssea/genética , Criança , Pré-Escolar , Desoxirribonucleases de Sítio Específico do Tipo II/genética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Increased osteoclast-mediated bone resorption is characteristic of osteoporosis, malignant bone disease and inflammatory arthritis. Targeted deletion of Sirtuin1 (Sirt1), a key player in aging and metabolism, in osteoclasts results in increased osteoclast-mediated bone resorption in vivo, making it a potential novel therapeutic target to block bone resorption. Sirt1 activating compounds (STACs) were generated and were investigated in animal disease models and in humans however their mechanism of action was a source of controversy. We studied the effect of SRT2183 and SRT3025 on osteoclastogenesis in bone-marrow derived macrophages (BMMs) in vitro, and discovered that these STACs inhibit RANKL-induced osteoclast differentiation, fusion and resorptive capacity without affecting osteoclast survival. SRT2183 and SRT3025 activated AMPK, increased Sirt1 expression and decreased RelA/p65 lysine310 acetylation, critical for NF-κB activation, and an established Sirt1 target. However, inhibition of osteoclastogenesis by these STACs was also observed in BMMs derived from sirt1 knock out (sirt1-/-) mice lacking the Sirt1 protein, in which neither AMPK nor RelA/p65 lysine 310 acetylation was affected, confirming that these effects require Sirt1, but suggesting that Sirt1 is not essential for inhibition of osteoclastogenesis by these STACs under these conditions. In sirt1 null osteoclasts treated with SRT2183 or SRT3025 Sirt3 was found to be down-regulated. Our findings suggest that SRT2183 and SRT3025 activate Sirt1 and inhibit RANKL-induced osteoclastogenesis in vitro however under conditions of Sirt1 deficiency can affect Sirt3. As aging is associated with reduced Sirt1 level and activity, the influence of STACs on Sirt3 needs to be investigated in vivo in animal and human disease models of aging and osteoporosis.
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Anilidas/farmacologia , Células da Medula Óssea/fisiologia , Regulação para Baixo , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Macrófagos/citologia , Osteoclastos/fisiologia , Ligante RANK/fisiologia , Sirtuína 1/fisiologia , Sirtuína 3/fisiologia , Tiazóis/farmacologia , Animais , Linhagem Celular , Feminino , CamundongosRESUMO
OBJECTIVE: Distal radius fracture (DRF) in postmenopausal women is often the first clinical sign of osteoporosis (OP). Despite the availability of effective treatments, only a minority of patients who sustain a fragility fracture are tested for OP. The purpose of this study was to examine whether a simple intervention by the hospital staff increases rates of OP workup. MATERIALS AND METHODS: We conducted a prospective randomized clinical trial. Ninety nine patients after DRF were randomized to two groups. Both groups were contacted after their fracture and were asked to answer a questionnaire and were informed about the possible relationship between DRF and OP. In the intervention group, patients were sent an explanatory pamphlet and a letter to their primary care physician. An additional survey was conducted to establish whether the intervention improved the number of patients who undergo OP workup. RESULTS: The intervention increased the proportion of patients who turned to their primary care physician from 22.9% to 68.6%, and increased the proportion of patients undergoing OP workup from 14.3% to 40% (p < 0.001). CONCLUSION: Women with DRF who receive an explanation about possible OP implications and are sent explanatory materials are more likely to undergo OP workup.
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Osteoporose/diagnóstico , Cooperação do Paciente , Educação de Pacientes como Assunto , Atenção Primária à Saúde/estatística & dados numéricos , Fraturas do Rádio/etiologia , Resina de Colestiramina , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/terapia , Folhetos , Pós-Menopausa , Estudos Prospectivos , Encaminhamento e ConsultaRESUMO
Estrogen deficiency leads to rapid bone loss and skeletal fragility. Sclerostin, encoded by the sost gene, and a product of the osteocyte, is a negative regulator of bone formation. Blocking sclerostin increases bone mass and strength in animals and humans. Sirtuin1 (Sirt1), a player in aging and metabolism, regulates bone mass and inhibits sost expression by deacetylating histone 3 at its promoter. We asked whether a Sirt1-activating compound could rescue ovariectomy (OVX)-induced bone loss and biomechanical deterioration in 9-week-old C57BL/6 mice. OVX resulted in a substantial decrease in skeletal Sirt1 expression accompanied by an increase in sclerostin. Oral administration of SRT3025, a Sirt1 activator, at 50 and 100 mg/kg·d for 6 weeks starting 6 weeks after OVX fully reversed the deleterious effects of OVX on vertebral bone mass, microarchitecture, and femoral biomechanical properties. Treatment with SRT3025 decreased bone sclerostin expression and increased cortical periosteal mineralizing surface and serum propeptide of type I procollagen, a bone formation marker. In vitro, in the murine long bone osteocyte-Y4 osteocyte-like cell line SRT3025 down-regulated sclerostin and inactive ß-catenin, whereas a reciprocal effect was observed with EX-527, a Sirt1 inhibitor. Sirt1 activation by Sirt1-activating compounds is a potential novel pathway to down-regulate sclerostin and design anabolic therapies for osteoporosis concurrently ameliorating other metabolic and age-associated conditions.
Assuntos
Ativadores de Enzimas/administração & dosagem , Glicoproteínas/genética , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo , Ovariectomia/efeitos adversos , Sirtuína 1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Regulação para Baixo , Feminino , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Camundongos Endogâmicos C57BL , Osteoporose Pós-Menopausa/enzimologia , Osteoporose Pós-Menopausa/fisiopatologia , Sirtuína 1/genéticaRESUMO
OBJECTIVE: Osteoporosis is often under-treated, and hip fracture is frequently its first manifestation. Hospitalization for a hip fracture is an opportunity to initiate osteoporosis treatment. The aim of this study was to investigate whether a simple intervention improves the implementation rate of a recommended osteoporosis treatment. METHODS: One hundred elderly patients admitted with low-impact hip fracture were given a 10 minute explanation about osteoporosis and its treatment during their postoperative hospital stay. In addition, the patients received an explanatory brochure and a letter to their primary care physician that included an article on fracture rate reduction with osteoporosis treatment. Implementation of therapy was assessed by a telephone survey 3 and 6 months postoperatively. The patients who had not received treatment at 3 months were given a repeated explanation. The historical control group was comprised of 100 hip fracture patients with similar demographic characteristics, who were operated on and discharged with the standard care recommendations for osteoporosis prevention. RESULTS: At the 3 month follow-up, the therapy rate in both groups was similar (19%). Fifty-eight percent of the patients in the study group had no recollection of the intervention. However, after a repeated explanation, at the 6 month follow-up, 39% of the intervention group had received drug therapy for fracture prevention (P<.001). CONCLUSION: A simple intervention enlisting the patients' help to involve their primary care physician can increase treatment rates for osteoporosis following a hip fracture. During the immediate postoperative period, the patients and their families have difficulty implementing the recommendations. Therefore, repeated communications are recommended.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Fraturas do Quadril/etiologia , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/etiologia , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea , Calcifediol/sangue , Atenção à Saúde , Feminino , Fraturas do Quadril/sangue , Humanos , Masculino , Osteoporose/sangue , Osteoporose/complicações , Fraturas por Osteoporose/sangue , Estudos ProspectivosRESUMO
OBJECTIVE: To investigate whether human immunodeficiency virus (HIV) infection or its treatment is a risk factor for thyroid dysfunction and whether thyroid function changes over time in 2 distinct subpopulations with HIV or acquired immunodeficiency syndrome (AIDS) in Israel: Ethiopian immigrants and Israeli patients. METHODS: Serum thyroid-stimulating hormone (TSH) and free thyroxine levels were determined in HIV carriers undergoing follow-up at the Hadassah-Hebrew University Medical Center HIV clinic in Jerusalem, Israel, and these thyroid measurements were correlated with clinical and laboratory variables pertaining to their disease, including disease duration, drug therapy, viral load, CD4 count, low-density lipoprotein cholesterol, and creatine kinase. Serum samples stored at -20°C from the time of referral were tested as well. RESULTS: We recruited 121 consecutive patients with HIV or AIDS for this study: 60 Ethiopians and 61 Israeli patients. Of the 121 patients, 4 (3%) had abnormal thyroid function-subclinical hypothyroidism in 2, overt hypothyroidism in 1, and overt hyperthyroidism in 1. Previously stored serum samples were available for 60 of the 121 patients and revealed 2 additional patients with subclinical hypothyroidism, whose TSH has normalized in the subsequent test. Throughout the follow-up period of 3.2 ± 1.9 years, the mean TSH level remained unchanged in the Israeli cohort but significantly declined in the Ethiopian cohort. CONCLUSION: Thyroid function abnormalities were uncommon in these Israeli patients with HIV or AIDS. This finding does not support the need for routine thyroid function tests in this patient population. The decline in TSH level in the Ethiopian population over time probably represents a shift from an iodine-deficient to an iodine-sufficient country.
Assuntos
Síndrome da Imunodeficiência Adquirida/etnologia , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Infecções por HIV/etnologia , Infecções por HIV/fisiopatologia , Glândula Tireoide/fisiopatologia , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , Terapia Antirretroviral de Alta Atividade , Estudos Transversais , Etiópia/etnologia , Feminino , Seguimentos , Infecções por HIV/tratamento farmacológico , Humanos , Hipertireoidismo/epidemiologia , Hipertireoidismo/fisiopatologia , Hipotireoidismo/epidemiologia , Hipotireoidismo/fisiopatologia , Incidência , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Sirt1, the mammalian ortholog of the yeast Sir2 (silent information regulator 2), was shown to play an important role in metabolism and in age-associated diseases, but its role in skeletal homeostasis and osteoporosis has yet not been studied. Using 129/Sv mice with a germline mutation in the Sirt1 gene, we demonstrate that Sirt1 haplo-insufficient (Sirt1(+/-)) female mice exhibit a significant reduction in bone mass characterized by decreased bone formation and increased marrow adipogenesis. Importantly, we identify Sost, encoding for sclerostin, a critical inhibitor of bone formation, as a novel target of Sirt1. Using chromatin immunoprecipitation analysis, we reveal that Sirt1 directly and negatively regulates Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter. Sost down-regulation by small interfering RNA and the administration of a sclerostin-neutralizing antibody restore gene expression of osteocalcin and bone sialoprotein as well as mineralized nodule formation in Sirt1(+/-) marrow-derived mesenchymal stem cells induced to osteogenesis. These findings reveal a novel role for Sirt1 in bone as a regulator of bone mass and a repressor of sclerostin, and have potential implications suggesting that Sirt1 is a target for promoting bone formation as an anabolic approach for treatment of osteoporosis.
Assuntos
Densidade Óssea , Glicoproteínas/antagonistas & inibidores , Osteogênese , Sirtuína 1/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Medula Óssea , Feminino , Regulação da Expressão Gênica , Mutação em Linhagem Germinativa , Peptídeos e Proteínas de Sinalização Intercelular , Células-Tronco Mesenquimais , Camundongos , Osteoporose , Sirtuína 1/genéticaRESUMO
OBJECTIVE: Alzheimer's disease (AD) and vascular dementia (VaD) are the main causes of dementia. Postmenopausal estrogen deficiency was suggested as a contributor to cognitive decline; however, replacement therapy failed to prove beneficial in its prevention or therapy. Sequence variants in the estrogen receptor alpha gene (ESR1) and beta gene (ESR2) may alter the effects of estrogen. METHODS: This is a case-control association study of sporadic AD, VaD, and single-nucleotide polymorphisms in ESR1 (rs2234693 and rs9340799), the TA dinucleotide repeat in the ESR1 promoter, and the rs4986938 single-nucleotide polymorphism in ESR2. Two hundred forty-six women (118 AD, age 83 +/- 7; 60 VaD, age 82 +/- 6; and 68 cognitively intact, age 81 +/- 7) residing in nursing homes were studied. The association of genotypes and AD or VaD was determined by logistic regression analysis adjusted for age and ethnic origin. RESULTS: An association of VaD and ESR2 rs4986938 was found. Carriers of each A allele had a 1.7 increased risk compared to carriers of the G allele (odds ratio 1.71, 95% confidence interval 1-2.95). The ApoE epsilon 4 allele was associated with AD (odds ratio 3.35, confidence interval 1.44-7.82), but not with VaD. No association of AD or VaD with ESR1 genotypes or haplotypes was detected. CONCLUSIONS: The ESR2 rs4986938 polymorphism is associated with susceptibility for VaD in elderly Jewish women. These results need to be confirmed in replicate studies in other populations.
Assuntos
Demência Vascular/genética , Receptor beta de Estrogênio/genética , Etnicidade/genética , Predisposição Genética para Doença , Variação Genética , Idoso de 80 Anos ou mais , Alelos , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Heterozigoto , Humanos , Israel , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
INTRODUCTION: Osteopenia is a common complication of human inflammatory bowel disease (IBD). We evaluated the contribution of colonic inflammation to osteopenia and its mechanism in a murine colitis model. METHODS: Colitis was induced by adding dextran sodium sulfate (DSS) to the drinking water for 2 weeks to nine-week-old Balb/C male mice. 5% DSS was added on the first week and was reduced to 2.5% on the second week. Age- and sex-matched Balb/C mice served as the control group. Indices of femoral bone mass and architecture were determined by micro computed tomography (muCT). Bone formation parameters and osteoclast number were determined by dynamic histomorphometry. The degree of colonic inflammation was assessed by a clinical disease activity index, and colonic mucosal myeloperoxidase activity. RESULTS: DSS-treated mice exhibited a significantly lower bone mass compared to controls as indicated by decreased trabecular bone volume (BV/TV) of 32%. This reduction was accompanied by decreased trabecular number (23%) and connectivity density (37%) compared to the controls. No changes were observed in cortical bone indices. Osteopenia resulted from suppressed bone formation, as indicated by decreased trabecular double-labeled surface (dL%) of 90%, mineralizing surface (MS) of 62%, and bone formation rate (BFR) of 67%, and increased bone resorption as indicated by a 34% increase in osteoclast number in DSS-treated mice compared to the controls. Myeloperoxidase activity inversely correlated with trabecular BV/TV (r=-0.67, p=0.02), trabecular number (r=-0.86, p=0.0008) and connectivity density (r=-0.63, p=0.03). Myeloperoxidase activity inversely correlated with the bone formation indices: dL%, MS, and BFR (r=-0.79, p=0.007, r=-0.84, p=0.002, r=-0.83, p=0.003, respectively). CONCLUSIONS: DSS-induced colitis is associated with reduced femoral bone mass and altered micro architecture, which results from suppressed bone formation and increased bone resorption. The decrease in indices of bone mass, structure and formation are directly linked to the degree of colonic mucosal inflammation. DSS-induced colitis can be used to study pharmacological interventions for bone loss in colitis.