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2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid (EC), acting as a full agonist at both CB1 and CB2 cannabinoid receptors. It is synthesized on demand in postsynaptic membranes through the sequential action of phosphoinositide-specific phospholipase Cß1 (PLCß1) and diacylglycerol lipase α (DAGLα), contributing to retrograde signaling upon interaction with presynaptic CB1. However, 2-AG production might also involve various combinations of PLC and DAGL isoforms, as well as additional intracellular pathways implying other enzymes and substrates. Three other alternative pathways of 2-AG synthesis rest on the extracellular cleavage of 2-arachidonoyl-lysophospholipids by three different hydrolases: glycerophosphodiesterase 3 (GDE3), lipid phosphate phosphatases (LPPs), and two members of ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPP6-7). We propose the names of AlterAG-1, -2, and -3 for three pathways sharing an ectocellular localization, allowing them to convert extracellular lysophospholipid mediators into 2-AG, thus inducing typical signaling switches between various G-protein-coupled receptors (GPCRs). This implies the critical importance of the regioisomerism of both lysophospholipid (LPLs) and 2-AG, which is the object of deep analysis within this review. The precise functional roles of AlterAGs are still poorly understood and will require gene invalidation approaches, knowing that both 2-AG and its related lysophospholipids are involved in numerous aspects of physiology and pathology, including cancer, inflammation, immune defenses, obesity, bone development, neurodegeneration, or psychiatric disorders.
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Ácidos Araquidônicos , Endocanabinoides , Glicerídeos , Lisofosfolipídeos , Transdução de Sinais , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Lisofosfolipídeos/metabolismo , Humanos , Ácidos Araquidônicos/metabolismo , Animais , Diester Fosfórico Hidrolases/metabolismoRESUMO
INTRODUCTION: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) features. PWS is a neurodevelopmental disorder clinically characterized by endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of the oxytocin (OXT) on it, have never been investigated in human neurons. METHODS: We studied the methylation marks in induced pluripotent stem-derived dopaminergic neurons carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neuron differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from the iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in these iPSC-derived dopaminergic neurons differentiated with or without OXT. RESULTS: The analysis revealed that 153,826 cytosines were differentially methylated between SNORD116 MD neurons and control neurons. Among the differentially methylated genes, we determined a list of genes also differentially expressed. Enrichment analysis of this list encompassed the dopaminergic system with COMT and SLC6A3. COMT displayed hypermethylation and under-expression in SNORD116 MD, and SLC6A3 displayed hypomethylation and over-expression in SNORD116 MD. RT-qPCR confirmed significant over-expression of SLC6A3 in SNORD116 MD neurons. Moreover, the expression of this gene was significantly decreased in the case of OXT adjunction during the differentiation. CONCLUSION: SNORD116 MD dopaminergic neurons displayed differential methylation and expression in the COMT and SLC6A3 genes, which are related to dopaminergic clearance.
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Bone fracture healing is a complex biological process involving four phases coordinated over time: hematoma formation, granulation tissue formation, bony callus formation, and bone remodelling. Bone fractures represent a significant health problem, particularly among the elderly population and patients with comorbidities. Therapeutic strategies proposed to treat such fractures include the use of autografts, allografts, and tissue engineering strategies. It has been shown that bone morphogenetic protein 2 (BMP-2) has a therapeutic potential to enhance fracture healing. Despite the clinical efficacy of BMP-2 in osteoinduction and bone repair, adverse side effects and complications have been reported. Therefore, in this in vitro study, we propose the use of a disaccharide compound (DP2) to improve the mineralisation process. We first evaluated the effect of DP2 on primary human osteoblasts (HOb), and then investigated the mechanisms involved. Our findings showed that (i) DP2 improved osteoblast differentiation by inducing alkaline phosphatase activity, osteopontin, and osteocalcin expression; (ii) DP2 induced earlier in vitro mineralisation in HOb cells compared to BMP-2 mainly by earlier activation of Runx2; and (iii) DP2 is internalized in HOb cells and activates the protein kinase C signalling pathway. Consequently, DP2 is a potential therapeutical candidate molecule for bone fracture repair.
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AIM: To describe the presenting features, bone characteristics and molecular genetics in a large monocentric cohort of children and young adults with idiopathic primary osteoporosis. METHODS: Sixty-six patients (19 children, 47 adults; 28 males, 38 females; age at referral: 3.8 to 65 years) diagnosed with primary osteoporosis were included in this study; patients with features of osteogenesis imperfecta or other known syndromes associated with osteoporosis were excluded. For each patient, the following data were collected by retrospective chart review: family and personal history of fracture and osteoporosis, mineral homeostasis parameters and markers of bone formation and resorption, bone mineral density (BMD) of the lumbar spine (LS-BMD), the total body less head (TB-BMD), and total hip levels (TH-BMD) measured by DXA. As part of the initial assessment process, a bone fragility gene panel sequencing was performed in all of these patients. RESULTS: There was a higher predominance of males in the children (63%) and of females in the adults (66%) (p = 0.030). Compared to the adults, the children had a significantly lower frequency of vertebral fractures (26 vs 57%, p = 0.022) and a higher frequency of peripheral fractures (84 vs 53%; p = 0.019). Bone fragility gene panel sequencing allowed the identification of the heterozygous pathogenic variant in 27% of patients (most frequently in LRP5, WNT1 and COL1A1 or 2 genes) and the heterozygous p.(Val667Met) LRP5 variant in 11% of them. The frequency of pathogenic variants tended to be higher in the children compared to the adults without reaching statistical significance (42 vs 19%; p = 0.053). The frequency of the p.(Val667Met) LRP5 variant was similar in children and adults. No significant differences were found regarding the various clinical, biological and radiological characteristics of the patients according to genotype. CONCLUSION: In this study, we reported the presenting features and bone characteristics in a large cohort of children and young adults with idiopathic primary osteoporosis. Bone fragility gene panel sequencing allowed the identification of genetic variants in a significant proportion of these patients. Molecular diagnosis in these patients is important in order to be able to offer genetic counselling and organise patient management.
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BACKGROUND: Adolescents with idiopathic scoliosis display high ghrelin levels. As hyperghrelinemia is found in patients with PWS and early-onset scoliosis (EOS) is highly prevalent in these patients, our aims were to explore (1) whether ghrelin levels differ between those with and without EOS and correlate with scoliosis severity, and (2) whether ghrelin levels in the first year of life are associated with the later development of EOS. METHODS: We used a case control study design for the first question and a longitudinal design for the second. Patients with PWS having plasma ghrelin measurements recorded between 2013 and 2018 in our database were selected and 30 children < 10 years old with EOS and 30 age- and BMI-matched controls without EOS were included. The Cobb angle at diagnosis was recorded. In addition, 37 infants with a ghrelin measurement in the first year of life were followed until 4 years of age and assessed for EOS. Total ghrelin (TG), acylated (AG) and unacylated ghrelin (UAG), and the AG/UAG ratio were analyzed. RESULTS: EOS children had an AG/UAG ratio statistically significantly lower than controls. The Cobb angle was positively correlated with TG and UAG. TG and AG in the first year of life were higher in infants who later develop EOS without reaching a statistically significant difference. CONCLUSIONS: Our results suggest that ghrelin may play a role in the pathophysiology of EOS in PWS. Higher ghrelinemia in the first year of life required careful follow-up for EOS.
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Síndrome de Prader-Willi , Escoliose , Adolescente , Biomarcadores , Estudos de Casos e Controles , Criança , Grelina , Humanos , LactenteRESUMO
PURPOSE: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction due to deficiency of imprinted genes located on the 15q11-q13 chromosome. Among them, the SNORD116 gene appears critical for the expression of the PWS phenotype. We aimed to clarify the role of SNORD116 in cellular and animal models with regard to growth hormone therapy (GHT), the main approved treatment for PWS. METHODS: We collected serum and induced pluripotent stem cells (iPSCs) from GH-treated PWS patients to differentiate into dopaminergic neurons, and in parallel used a Snord116 knockout mouse model. We analyzed the expression of factors potentially linked to GH responsiveness. RESULTS: We found elevated levels of circulating IGFBP7 in naive PWS patients, with IGFBP7 levels normalizing under GHT. We found elevated IGFBP7 levels in the brains of Snord116 knockout mice and in iPSC-derived neurons from a SNORD116-deleted PWS patient. High circulating levels of IGFBP7 in PWS patients may result from both increased IGFBP7 expression and decreased IGFBP7 cleavage, by downregulation of the proconvertase PC1. CONCLUSION: SNORD116 deletion affects IGFBP7 levels, while IGFBP7 decreases under GHT in PWS patients. Modulation of the IGFBP7 level, which interacts with IGF1, has implications in the pathophysiology and management of PWS under GHT.
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Células-Tronco Pluripotentes Induzidas , Síndrome de Prader-Willi , Animais , Hormônio do Crescimento , Humanos , Camundongos , Neurônios , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/genética , RNA Nucleolar PequenoRESUMO
Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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Monócitos/efeitos da radiação , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Receptor Tipo 1 de Melanocortina/genética , Transcriptoma/efeitos da radiação , Vitamina D/sangue , Linfócitos B/efeitos da radiação , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Humanos , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/radioterapia , Fenótipo , Fototerapia , Recidiva , Índice de Gravidade de Doença , Luz Solar , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Transcriptoma/genéticaRESUMO
We have examined the Acylated Ghrelin (AG)/Gi pathway in different human osteoblastic cell lines. We have found that: 1) AG induces differentiation/mineralization only in mature osteoblasts; 2) the expression of GHS-R1a increases up to the mature cell stage, 3) the action is mediated via the GHS-R/Gi/cAMP pathway only in mature osteoblasts, and 4) osteoblastic cells from adolescent idiopathic scoliosis (AIS) are resistant to the AG/Gi/cAMP pathway. Altogether, these results suggested that AG uses the GHS-R1a/Gi/cAMP pathway to induce differentiation in mature osteoblasts only. This pathway is impaired in AIS osteoblasts. Understanding AG-specific pathways involved in normal and pathological osteoblasts may be useful for developing new treatments for pathologies such as AIS or osteoporosis.
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HIV-1 infection is frequently associated with low bone density, which can progress to osteoporosis leading to a high risk of fractures. Only a few mechanisms have been proposed to explain the enhanced osteolysis in the context of HIV-1 infection. As macrophages are involved in bone homeostasis and are critical host cells for HIV-1, we asked whether HIV-1-infected macrophages could participate in bone degradation. Upon infection, human macrophages acquired some osteoclast features: they became multinucleated, upregulated the osteoclast markers RhoE and ß3 integrin, and organized their podosomes as ring superstructures resembling osteoclast sealing zones. However, HIV-1-infected macrophages were not fully differentiated in osteoclasts as they did not upregulate NFATc-1 transcription factor and were unable to degrade bone. Investigating whether infected macrophages participate indirectly to virus-induced osteolysis, we showed that they produce RANK-L, the key osteoclastogenic cytokine. RANK-L secreted by HIV-1-infected macrophages was not sufficient to stimulate multinucleation, but promoted the protease-dependent migration of osteoclast precursors. In conclusion, we propose that, by stimulating RANK-L secretion, HIV-1-infected macrophages contribute to create a microenvironment that favors the recruitment of osteoclasts, participating in bone disorders observed in HIV-1 infected patients.
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Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Macrófagos/metabolismo , Macrófagos/virologia , Osteoclastos/imunologia , Ligante RANK/metabolismo , Biomarcadores , Movimento Celular/imunologia , Células Cultivadas , Imunofluorescência , Expressão Gênica , Células Gigantes/virologia , Infecções por HIV/imunologia , Humanos , Macrófagos/imunologia , OsteóliseRESUMO
Lysphosphatidic acid (LPA) is a major natural bioactive lipid mediator whose biological functions affect multiple organs. These include bone as demonstrated by global Lpar1-knockout mice (Lpar1-/-) which present a bone growth defect. LPA acts on all bone cells including osteoblasts, that are responsible for bone formation, and osteoclasts, which are specialized cells that resorb bone. LPA appears as a potential new coupling molecule during bone remodeling. LPA1 is the most ubiquitous LPA receptor among the six LPA receptor family members (LPA1-6). To better understand the specific role of LPA via its receptor LPA1 in osteoblastic cell lineage we generated osteoblast-specific Lpar1 knockout mice (Lpar1-∆Ob) by crossing Lpar1flox/flox and Osx:Cre+ mouse lines. Lpar1-∆Ob mice do not recapitulate the bone defects of Lpar1-/- mice but revealed reduced bone mineralization and decreased cortical thickness, as well as increased bone porosity associated with an augmentation in the lacunae areas of osteocyte and their apoptotic yield. In vitro, primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts revealed a remarkable premature expression of alkaline phosphatase, reduced cell proliferation associated with decreased YAP-P nuclear accumulation, and reduced mineralization activity. Osteocyte specification is markedly impaired as demonstrated by reduced expression of early (E11) and late (DMP1, DKK1, SOST) osteocyte markers ex vivo in enriched osteocytic fractions of Lpar1-∆Ob mouse bone explants. In addition, E11 expression and dendrite formation induced by FGF2 are markedly impaired in both primary Lpar1-∆Ob and immortalized cl1-Ob-Lpar1-/- osteoblasts. Taken together these results suggest a new role for LPA in bone mass control via bone mineralization and osteocyte function.
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Osteoblastos/metabolismo , Osteócitos/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Densidade Óssea , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteogênese , Receptores de Ácidos Lisofosfatídicos/deficiência , Receptores de Ácidos Lisofosfatídicos/genéticaRESUMO
Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins. In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.
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Condrócitos/metabolismo , Fator de Crescimento Insulin-Like I/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Animais , Butadienos/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Modelos Animais de Doenças , Lâmina de Crescimento/anormalidades , Lâmina de Crescimento/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/administração & dosagem , Sistema de Sinalização das MAP Quinases , Nitrilas/administração & dosagem , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/patologiaRESUMO
BACKGROUND: Vitamin D deficiency is associated with an increased risk of Alzheimer's disease and increased beta-amyloid (Aß) in animals. Hence we sought to investigate the relationship between plasma 25-hydroxyvitamin D (25(OH)D) and cerebral Aß in older adults with subjective memory complaints. METHODS: This is a secondary analysis of the Multidomain Alzheimer Preventive Trial. Participants were 178 dementia-free individuals aged 70 years or older with data on plasma 25(OH)D and cerebral Aß load assessed by [18F]-florbetapir positron emission tomography. Plasma 25(OH)D was measured at study baseline using a commercially available electro-chemiluminescence competitive binding assay. Standard uptake value ratios (SUVRs) were generated using the cerebellum as a reference. Brain regions assessed included the cortex, anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval centre and temporal cortex. Associations were explored using fully adjusted multiple linear regression models. RESULTS: Participants had a mean (SD) age of 76.2 years (4.4) and 59.6% were female. The mean (SD) plasma 25(OH)D level was 22.4 ng/ml (10.8) and the mean (SD) cortical SUVR was 1.2 (0.2). We did not find any cross-sectional associations (p > 0.05) between baseline 25(OH)D levels and Aß in any of the brain regions studied. CONCLUSIONS: These preliminary results suggest that circulating 25(OH)D is not associated with cerebral Aß in older adults. Further longitudinal studies with the measurement of mid-life vitamin D status are required to explore the relationship between vitamin D and Aß accrual over time, thereby circumventing the shortfalls of a cross-sectional study.
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Envelhecimento/sangue , Envelhecimento/patologia , Córtex Cerebral/metabolismo , Demência/diagnóstico , Vitamina D/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/metabolismo , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Etilenoglicóis/metabolismo , Feminino , Humanos , Modelos Lineares , Masculino , Testes de Estado Mental e Demência , Tomografia por Emissão de Pósitrons , Vitamina D/sangueRESUMO
BACKGROUND: Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication. METHODS AND FINDINGS: To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals. CONCLUSION: This study demonstrate that achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.
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Acondroplasia/complicações , Acondroplasia/genética , Obesidade/etiologia , Obesidade/prevenção & controle , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/uso terapêutico , Acondroplasia/diagnóstico , Acondroplasia/tratamento farmacológico , Adolescente , Animais , Biomarcadores , Glicemia , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Transgênicos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/farmacologia , Prevenção SecundáriaRESUMO
Bone deficits are frequent in HIV-1-infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1-induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef.
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Reabsorção Óssea/etiologia , Infecções por HIV/complicações , HIV-1/fisiologia , Osteoclastos/virologia , Actinas/metabolismo , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Osso e Ossos/metabolismo , Adesão Celular , Feminino , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Camundongos , Osteoclastos/citologia , Osteoclastos/metabolismo , Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismoRESUMO
Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4â¯months before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1â¯=â¯30â¯pmol/l (20.4-41.1), T2â¯=â¯37.4â¯pmol/l (29.8-49.4), pâ¯<â¯0.0001, T3â¯=â¯42â¯pmol/l (33.8-55.5), pâ¯<â¯0.0001 sclerostin medians (IQR): T1â¯=â¯0.57 (0.47-0.69), T2â¯=â¯0.62â¯ng/ml (0.53-0.79), pâ¯<â¯0.0001, T3â¯=â¯n0.64â¯ng/ml (0.56-0.79), pâ¯=â¯0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.
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Biomarcadores Tumorais/análise , Proteínas Morfogenéticas Ósseas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Mieloma Múltiplo/patologia , Proteínas Adaptadoras de Transdução de Sinal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
In a control population, we filed the 24-hour urinary calcium to set normal values, based on weight, BMI and menopause. By assessing calcium intake, 25OHD, PTH, CTX, GFR, we wanted to study how these could influence calcium excretion. A total of 317 subjects of 55.82 ± 12.6 years were studied: 249 women (210 were postmenopausal) and 66 men. Mean urinary calcium 24h was 4.07 ± 2.53 mmol: 3.99 ± 2.89 in men, 3.54 ± 2.44 in premenopausal women, 4.18 ± 2.42 in postmenopausal women. 24-hour urine calcium was lower in overweight subjects whether they are men or women. It was positively correlated to 25OHD, CTX, GFR, serum calcium and negatively to PTH, BMI and weight. In conclusion, urinary calcium was lower in overweight subjects, it increases after menopause. Dietary calcium intake seems little involved in explaining variations in urinary calcium which depends essentially on bone remodeling (CTX), GFR, levels of vitamin D and PTH.
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Cálcio/urina , Urinálise/normas , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Menopausa/urina , Pessoa de Meia-Idade , Valores de Referência , Fatores de Tempo , Urinálise/métodosRESUMO
BACKGROUND: A control study was designed to investigate circulating Ghrelin levels in adolescent girls with adolescent idiopathic scoliosis (AIS) and controls. Eating behavioral disorders, endocrine disorders, abnormal growth pattern and osteopenia have been well documented in AIS. Ghrelin is an orexigenic hormone produced by the stomach which reflects body weight changes and stimulates growth hormone secretion. Recently, it has been shown to be associated with bone metabolism and eating behavior. However, the circulating levels of ghrelin have never been evaluated in AIS patients. METHODS: Forty nine AIS girls and 15 controls were included. Anthropometric parameters and fasting circulating total ghrelin were measured. Curve severity was evaluated in AIS girls. The relationships between ghrelin and age, body weight, height, body mass index (BMI), BMI Z-score and corrected anthropometric parameters were analyzed in AIS girls and controls. RESULTS: There was no significant difference in body weight, height, BMI or BMI Z-score between AIS and controls. Serum ghrelin level was 1.8 fold higher in AIS girls than in controls. Elevation of ghrelin levels remained significant when corrected BMI or corrected BMI Z-score were considered. Unlike in controls, positive correlations were found between ghrelin and age in AIS girls with a gradual increase of circulating ghrelin with age. CONCLUSIONS: We have observed significantly higher circulating ghrelin levels in AIS than in controls with a positive correlation with age. This pilot-study suggests that ghrelin signaling might play a role in the initiation or development of AIS. Further studies are needed to validate theses results.
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INTRODUCTION: Can vitamin D deficiency be predicted by patient questionnaire? Does it lead to secondary hyperparathyroidism that may cause excessive bone resorption? We studied non-osteoporotic subjects in their fifties, in whom vitamin D levels are often tested. PATIENTS AND METHODS: Patients hospitalised for degenerative osteoarthritis or consulting for assessment of menopause, without renal failure and not treated with vitamin D, completed a questionnaire on sun exposure and underwent measurement of serum calcium, creatinine, 25OH vitamin D, PTH and CTX. RESULTS: Five hundred and twenty-six subjects, mean age 54.6 years (71% women), were investigated throughout the year. 25OH vitamin D levels were correlated with sun exposure and varied according to the month of the year, unlike PTH and CTX levels. From November to May, over 90% of subjects had 25OH vitamin D levels<30ng/mL. Of the subjects who did not expose their face, arms and legs to the sun for at least 20min/day, 94% had 25OH vitamin D levels<30ng/mL. PTH levels were negatively correlated with those of 25OH vitamin D. Serum CTX levels were not correlated with PTH or 25OH vitamin D. Only 13% of subjects presented with secondary hyperparathyroidism, characterised by serum calcium<2.55mmol/L and PTH>65pg/mL, associated with increased CTX levels. CONCLUSION: Vitamin D deficiency can be predicted by patient questionnaire. It very rarely leads to secondary hyperparathyroidism.
Assuntos
Hiperparatireoidismo Secundário/diagnóstico , Inquéritos e Questionários , Deficiência de Vitamina D/diagnóstico , Cálcio/sangue , Estudos de Coortes , Colágeno Tipo I/sangue , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Hiperparatireoidismo Secundário/etiologia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Peptídeos/sangue , Prognóstico , Vitamina D/sangue , Deficiência de Vitamina D/complicaçõesRESUMO
Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutation in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1), leading to transforming growth factor-beta (TGF-ß) signaling dysregulation. Although decreased axial and peripheral bone mineral density (BMD) has been reported in adults with MFS, data about the evolution of bone mass during childhood and adolescence are limited. The aim of the present study was to evaluate bone and muscle characteristics in children, adolescents, and young adults with MFS. The study population included 48 children and young adults (22 girls) with MFS with a median age of 11.9 years (range 5.3 to 25.2 years). The axial skeleton was analyzed at the lumbar spine using dual-energy X-ray absorptiometry (DXA), whereas the appendicular skeleton (hand) was evaluated using the BoneXpert system (with the calculation of the Bone Health Index). Muscle mass was measured by DXA. Compared with healthy age-matched controls, bone mass at the axial and appendicular levels and muscle mass were decreased in children with MFS and worsened from childhood to adulthood. Vitamin D deficiency (<50 nmol/L) was found in about a quarter of patients. Serum vitamin D levels were negatively correlated with age and positively correlated with lumbar spine areal and volumetric BMD. Lean body mass (LBM) Z-scores were positively associated with total body bone mineral content (TB-BMC) Z-scores, and LBM was an independent predictor of TB-BMC values, suggesting that muscle hypoplasia could explain at least in part the bone loss in MFS. Patients with a FBN1 premature termination codon mutation had a more severe musculoskeletal phenotype than patients with an inframe mutation, suggesting the involvement of TGF-ß signaling dysregulation in the pathophysiologic mechanisms. In light of these results, we recommend that measurement of bone mineral status should be part of the longitudinal clinical investigation of MFS children.
Assuntos
Envelhecimento , Genótipo , Síndrome de Marfan , Proteínas dos Microfilamentos/genética , Músculo Esquelético , Coluna Vertebral , Absorciometria de Fóton , Adulto , Envelhecimento/genética , Envelhecimento/patologia , Densidade Óssea , Criança , Pré-Escolar , Códon de Terminação , Estudos Transversais , Feminino , Fibrilina-1 , Fibrilinas , Seguimentos , Humanos , Masculino , Síndrome de Marfan/diagnóstico por imagem , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologiaRESUMO
INTRODUCTION: A decrease of insulin-like growth factor-I levels (IGF-I) has been reported during the first trimester of pregnancy in women with acromegaly before the secretion of placental growth hormone (GH) progressively increases IGF-1 concentration. STUDY DESIGN: To evaluate variations of concentrations of IGF-1, insulin-like growth factor (IGF)-binding protein-3 (IGF-BP3) and GH during the first trimester of pregnancy in women with normal somatotroph function. PATIENTS AND METHODS: Sixteen women (median age 31 years) with as who were followed for benign thyroid disorders (n = 15) or prolactin-secreting microadenoma (n = 1) were evaluated before and in the first trimester of pregnancy. Serum concentrations of GH, IGF-1, IGF-BP3, TSH and estradiol (E2) were measured before and in the first trimester (5.4 ± 2.2 weeks of gestation). RESULTS: Before pregnancy, somatotroph and thyroid functions (median TSH 1.2 mU/L) were normal in all women. At the first trimester IGF-1 levels decreased significantly (before = 210 ng/mL, first trimester = 145 ng/mL, p < 0.001) with no significant change in GH (before = 1.5 ng/mL, first trimester = 0.84 ng/mL) or IGF-BP3 levels (before = 2.3 ng/mL, first trimester = 2.2 ng/mL), while estradiol levels increased significantly (before = 46.5 pg/100 mL, first trimester = 448.5 pg/100 mL, p < 0.001). CONCLUSION: In women with normal somatotroph function, IGF-1 levels decrease in the first trimester of pregnancy without changes in GH or IGF-BP3 levels. These results confirm liver resistance to GH as a consequence of the physiological increase of estrogens during the first trimester.