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INTRODUCTION: X-linked hypophosphatemia is an orphan disease of genetic origin and multisystem involvement. It is characterized by a mutation of the PHEX gene which results in excess FGF23 production, with abnormal renal and intestinal phosphorus metabolism, hypophosphatemia and osteomalacia secondary to chronic renal excretion of phosphate. Clinical manifestations include hypophosphatemic rickets leading to growth abnormalities and osteomalacia, myopathy, bone pain and dental abscesses. The transition of these patients to adult life continues to pose challenges to health systems, medical practitioners, patients and families. For this reason, the aim of this consensus is to provide a set of recommendations to facilitate this process and ensure adequate management and follow-up, as well as the quality of life for patients with X-linked hypophosphatemia as they transition to adult life. MATERIALS AND METHODS: Eight Latin American experts on the subject participated in the consensus and two of them were appointed as coordinators. The consensus work was done in accordance with the nominal group technique in 6 phases: (1) question standardization, (2) definition of the maximum number of choices, (3) production of individual solutions or answers, (4) individual question review, (5) analysis and synthesis of the information and (6) synchronic meetings for clarification and voting. An agreement was determined to exist with 80% votes in favor in three voting cycles. RESULTS AND DISCUSSION: Transition to adult life in patients with hypophosphatemia is a complex process that requires a comprehensive approach, taking into consideration medical interventions and associated care, but also the psychosocial components of adult life and the participation of multiple stakeholders to ensure a successful process. The consensus proposes a total of 33 recommendations based on the evidence and the knowledge and experience of the experts. The goal of the recommendations is to optimize the management of these patients during their transition to adulthood, bearing in mind the need for multidisciplinary management, as well as the most relevant medical and psychosocial factors in the region.
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Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Osteomalacia , Adulto , Humanos , Raquitismo Hipofosfatêmico Familiar/genética , Osteomalacia/genética , Osteomalacia/metabolismo , Consenso , Qualidade de Vida , Hipofosfatemia/genética , Hipofosfatemia/metabolismo , Fatores de Crescimento de Fibroblastos/genéticaRESUMO
PURPOSES: Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and ß-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene. METHODS: In a cross-sectional study, we measured the levels of FGF21 and ß-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and ß-Klotho were calculated. RESULTS: Baseline levels of FGF21 were similar, but baseline levels of ß-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and ß-Klotho levels than control subjects. There was a positive correlation between IGF1 and ß-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels. CONCLUSIONS: Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and ß-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.
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Nanismo Hipofisário , Adulto , Envelhecimento , Estudos Transversais , Fatores de Crescimento de Fibroblastos , Humanos , MasculinoRESUMO
Aging affects the body composition and balance of energy metabolism. Here, we collected in a single work several physiological parameters to show how aging and sex differences can influence energy homeostasis. Body mass index (BMI), Lee index, glucose tolerance, glycemia, and lipidogram in fasting were measured in male and female Wistar rats at the ages of 2, 6, 9, 12, and 18 months. We also measured the lipid profile, free fatty acids, glycerol, glycemia, leptin, adiponectin, insulin, corticosterone (CORT), prolactin (PRL), thyroid stimulated hormone, and triiodothyronine (T3) in 3- and 18-month-old rats of both sexes, fed ad libitum. Animals were classified as obese beginning at 2 months in males and 6 months in females. Aged male rats showed hyperglycemia and glucose intolerance compared to young males and old females. In the ad libitum condition, the 18-month males presented higher serum levels of triglycerides, total cholesterol, and free fatty acids than females. The 18-month-old females had higher PRL and CORT concentration than males, but insulin and T3 were higher in 18-month-old males than females. Our work demonstrated that aging processes on energy metabolism in rats is sex specific, with a better lipid profile and glucose tolerance in aged females.
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Envelhecimento/fisiologia , Composição Corporal , Metabolismo Energético , Hormônios Peptídicos/metabolismo , Caracteres Sexuais , Envelhecimento/metabolismo , Animais , Feminino , Glucose/metabolismo , Homeostase , Metabolismo dos Lipídeos , Masculino , Ratos , Ratos WistarRESUMO
The present study was designed to evaluate the relationship between bone traits [bone mineral density (BMD) and trabecular bone score (TBS)] and the accumulation of fat in adipose tissues [abdominal subcutaneous (SAT), visceral (VAT), marrow (MAT) and intrahepatic lipids (IHL)], as well as insulin resistance, in subjects with Cushing's disease (CD). The study included control (C = 27), paired (P = 16) and Cushing's disease (CD = 10) groups, which underwent biochemical assessment, dual X-ray absorptiometry, TBS, and magnetic resonance imaging to determine fat deposits. The CD group showed higher serum levels of glucose and insulin, as well as HOMA-IR values, but lower circulatory levels of osteocalcin, in comparison to C and P. The CD group exhibited lower L1-L4 BMD than P (P = 1.059 ± 0.141 vs CD = 0.935 ± 0.093 g/cm2, p < 0.05) (Fig 1A). The lumbar spine BMD from the C group was similar to the other groups. TBS was lower in CD than in P and C (C = 1.512±0.077 vs P = 1.405±0.150 vs CD = 1.135±0.136; p<0.05); there was also significant difference between C and P (p<0.05). MAT, VAT, and IHL were higher in CD than in C and P (p<0.05). Considering all subjects, there was a positive association between TBS with both lumbar spine BMD (R2 = 0.45; p<0.0001) and osteocalcin (R2 = 0.44; p = 0.05). TBS was negatively associated with MAT (R2 = 0.49; p = 0.01), VAT (R2 = 0.55; p<0.05), and HOMA-IR (R2 = 0.44; p<0.01). MAT was positively related with VAT (R2 = 0.44; p<0.01) and IHL (R2 = 0.41; p<0.05). In CD, insulin resistance and adipose tissue dysfunction, including high MAT, are active players in bone deterioration, as confirmed by lower lumbar spine BMD and lower TBS. Thus, our findings point to an additional component of the already well-known complex mechanisms of osteoporosis associated with hypercortisolism.
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Tecido Adiposo/patologia , Medula Óssea/patologia , Osso e Ossos/patologia , Síndrome Metabólica/complicações , Hipersecreção Hipofisária de ACTH/complicações , Adiponectina/metabolismo , Adulto , Peso Corporal , Densidade Óssea , Osso Esponjoso/patologia , Humanos , Resistência à Insulina , Leptina/metabolismo , Modelos Lineares , Lipídeos/análiseRESUMO
Anthropomorphic measures among type 1 diabetic patients are changing as the obesity epidemic continues. Excess fat mass may impact bone density and ultimately fracture risk. We studied the interaction between bone and adipose tissue in type 1 diabetes subjects submitted to two different clinical managements: (I) conventional insulin therapy or (II) autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST). The study comprised 3 groups matched by age, gender, height and weight: control (C = 24), type 1 diabetes (T1D = 23) and type 1 diabetes treated with AHST (T1D-AHST = 9). Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by dual X-ray absorptiometry (DXA). 1H Magnetic resonance spectroscopy was used to assess bone marrow adipose tissue (BMAT) in the L3 vertebra, and abdominal magnetic resonance imaging was used to assess intrahepatic lipids (IHL), visceral (VAT) and subcutaneous adipose tissue (SAT). Individuals conventionally treated for T1D were more likely to be overweight (C = 23.8 ± 3.7; T1D = 25.3 ± 3.4; T1D-AHST = 22.5 ± 2.2 Kg/m2; p > 0.05), but there was no excessive lipid accumulation in VAT or liver. Areal BMD of the three groups were similar at all sites; lumbar spine TBS (L3) was lower in type 1 diabetes (p < 0.05). Neither SAT nor VAT had any association with bone parameters. Bone marrow adipose tissue (BMAT) lipid profiles were similar among groups. BMAT saturated lipids were associated with cholesterol, whereas unsaturated lipids had an association with IGF1. Overweight and normal weight subjects with type 1 diabetes have normal areal bone density, but lower trabecular bone scores. Adipose distribution is normal and BMAT volume is similar to controls, irrespective of clinical treatment.
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Tecido Adiposo/diagnóstico por imagem , Medula Óssea/diagnóstico por imagem , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Absorciometria de Fóton , Adulto , Composição Corporal , Densidade Óssea , Remodelação Óssea , Osso e Ossos , Brasil , Osso Esponjoso/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/terapia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Gordura Intra-Abdominal/diagnóstico por imagem , Metabolismo dos Lipídeos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética , Gordura Subcutânea/diagnóstico por imagem , Transplante Autólogo , Adulto JovemRESUMO
Energy deprivation leads to a decrease in white adipose tissue and bone mineral density (BMD), while simultaneously inducing the expansion of marrow adipose tissue (MAT). In short bowel syndrome (SBS), parenteral nutrition mitigates the deterioration of nutritional status, including decreases in MAT. Osteoporosis is, however, a frequent complication of SBS. The objective of our study here was to evaluate the association of fat deposit sites (subcutaneous and visceral adipose tissues: intrahepatic lipid (IHL) and MAT) and the incretin glucagon-like peptide 1 (GLP1) with BMD in individuals with SBS. MAT was negatively correlated with lumbar spine BMD in normal individuals, but not in those in the SBS group, who otherwise showed a positive correlation between MAT and GLP1. In addition, in individuals with SBS, IHL was negatively associated with lumbar spine BMD and positively associated with C-terminal telopeptide of type 1 collagen (a serum biomarker of bone turnover). Caloric maintenance in individuals with SBS, therefore, seems to positively affect the relationship between MAT and BMD, which may be modulated, at least in part, by GLP1.
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Peptídeo 1 Semelhante ao Glucagon/metabolismo , Incretinas/metabolismo , Nutrição Parenteral , Síndrome do Intestino Curto/metabolismo , Síndrome do Intestino Curto/terapia , Tecido Adiposo/metabolismo , Adulto , Densidade Óssea , Medula Óssea/metabolismo , Remodelação Óssea , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/metabolismo , Síndrome do Intestino Curto/complicaçõesRESUMO
OBJECTIVES:: The present study was designed to evaluate the bone phenotypes and mechanisms involved in bone disorders associated with hepatic osteodystrophy. Hepatocellular disease was induced by carbon tetrachloride (CCl4). In addition, the effects of disodium pamidronate on bone tissue were evaluated. METHODS:: The study included 4 groups of 15 mice: a) C = mice subjected to vehicle injections; b) C+P = mice subjected to vehicle and pamidronate injections; c) CCl4+V = mice subjected to CCl4 and vehicle injections; and d) CCl4+P = mice subjected to CCl4 and pamidronate injections. CCl4 or vehicle was administered for 8 weeks, while pamidronate or vehicle was injected at the end of the fourth week. Bone histomorphometry and biomechanical analysis were performed in tibiae, while femora were used for micro-computed tomography and gene expression. RESULTS:: CCl4 mice exhibited decreased bone volume/trabecular volume and trabecular numbers, as well as increased trabecular separation, as determined by bone histomorphometry and micro-computed tomography, but these changes were not detected in the group treated with pamidronate. CCl4 mice showed increased numbers of osteoclasts and resorption surface. High serum levels of receptor activator of nuclear factor-κB ligand and the increased expression of tartrate-resistant acid phosphatase in the bones of CCl4 mice supported the enhancement of bone resorption in these mice. CONCLUSION:: Taken together, these results suggest that bone resorption is the main mechanism of bone loss in chronic hepatocellular disease in mice.
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Conservadores da Densidade Óssea/farmacologia , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Remodelação Óssea/efeitos dos fármacos , Difosfonatos/farmacologia , Hepatopatias/complicações , Animais , Doenças Ósseas Metabólicas/metabolismo , Reabsorção Óssea/metabolismo , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Tetracloreto de Carbono , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Hepatopatias/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoprotegerina/genética , Pamidronato , Fósforo/administração & dosagem , Ligante RANK/genética , Fosfatase Ácida Resistente a Tartarato/genética , Microtomografia por Raio-XRESUMO
BACKGROUND: Anthropometric models remain appropriate alternatives to estimate body composition of peripubertal populations. However, these traditional models do not consider other body components that undergo major changes during peripubertal growth spurt, with restrictions to a multicompartimental approach as a quantitative growth. DXA has great potential to determine pediatric body composition in more than one component (3-C), but has limited use in field settings. Thus, the aim of this study was to propose and validate an anthropometric model for simultaneous estimation of lean soft tissue (LST), bone mineral content (BMC) and fat mass (FM) in healthy girls, from a multivariate approach of densitometric technique, as the criterion method. METHODS: A sample of 84 Brazilian girls (7-17 years) was defined by chronological age and maturity offset. Whole total and regional DXA body scan were performed and, the components were defined (LST, BMC and FM) and considered as dependent variables. Twenty-one anthropometric measures were recorded as independent variables. From a multivariate regression, an anthropometric multicompartmental model was obtained. RESULTS: It was possible to predict DXA body components with only four predictive measurements: body weight (BW); supra-iliac skinfold (SiSk); horizontal abdominal skinfold (HaSk) and contracted arm circumference (CaCi) with high coefficients of determination and low estimation errors (LST = 0.6662657 BW - 0. 2157279 SiSk - 0.2069373 HaSk + 0.3411678 CaCi - 1.8504187; BMC = 0.0222185 BW - 0.1001097 SiSk - 0.0064539 HaSk - 0.0084785 CaCi + 0.3733974 and FM = 0.3645630 BW + 0.1000325 SiSk - 0.2888978 HaSk - 0.4752146 CaCi + 2.8461916). The cross-validation was confirmed through the sum of squares of residuals (PRESS) method, presenting accurate coefficients (Q2PRESS from 0.81 to 0.93) and reduced error reliability (SPRESS from 0.01 to 0.30). CONCLUSIONS: When sophisticated instruments are not available, this model provides valid estimates of multicompartmental body composition of girls in healthy Brazilian pediatric populations.
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BACKGROUND: Osteogenesis Imperfecta (OI) (OMIM %259450) is a heterogeneous group of inherited disorders characterized by increased bone fragility, with clinical severity ranging from mild to lethal. The majority of OI cases are caused by mutations in COL1A1 or COL1A2. Bruck Syndrome (BS) is a further recessively-inherited OI-like phenotype in which bone fragility is associated with the unusual finding of pterygia and contractures of the large joints. Notably, several studies have failed to show any abnormalities in the biosynthesis of collagen 1 in BS patientes. Evidence was obtained for a specific defect of the procollagen telopeptide lysine hydroxylation in BS, whereas mutations in the gene PLOD2 have been identified. Recently, several studies described FKBP10 mutations in OI-like and BS patients, suggesting that FKBP10 is a bonafide BS locus. METHODS: We analyzed the coding region and intron/exon boundaries of COL1A1, COL1A2, PLOD2 and FKBP10 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. Mononuclear cells obtained from the bone marrow of BS, OI patients and healthy donors were cultured and osteogenic differentiation was induced. The gene expression of osteoblast specific markers were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System. RESULTS: No mutations in COL1A1, COL1A2 or PLOD2 were found in BS patient. We found a homozygous 1-base-pair duplication (c.831dupC) that is predicted to produce a translational frameshift mutation and a premature protein truncation 17 aminoacids downstream (p.Gly278ArgfsX95). The gene expression of osteoblast specific markers BGLAP, COL1A1, MSX2, SPARC and VDR was evaluated by Real Time RT-PCR during differentiation into osteoblasts and results showed similar patterns of osteoblast markers expression in BS and healthy controls. On the other hand, when compared with OI patients, the expression pattern of these genes was found to be different. CONCLUSIONS: Our work suggests that the gene expression profiles observed during mesenchymal stromal cell differentiation into osteoblast are distinct in BS patients as compared to OI patients. The present study shows for the first time that genes involved in osteogenesis are differentially expressed in BS and OI patients.
Assuntos
Artrogripose/genética , Medula Óssea/patologia , Marcadores Genéticos/genética , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Osteogênese Imperfeita/genética , Adolescente , Adulto , Diferenciação Celular , Células Cultivadas , Criança , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Masculino , Osteogênese , Análise de Sequência de DNA/métodos , Adulto JovemRESUMO
Bone marrow harbors a significant amount of body adipose tissue (BMAT). While BMAT might be a source of energy for bone modeling and remodeling, its increment can also represent impairment of osteoblast differentiation. The relationship between BMAT, bone mass and insulin sensitivity is only partially understood and seems to depend on the circumstances. The present study was designed to assess the association of BMAT with bone mineral density in the lumbar spine as well as with visceral adipose tissue, intrahepatic lipids, HOMA-IR, and serum levels of insulin and glucose. This cross-sectional clinical investigation included 31 non-diabetic women, but 11 had a pre-diabetes status. Dual X-ray energy absorptiometry was used to measure bone mineral density and magnetic resonance imaging was used to assess fat deposition in BMAT, visceral adipose tissue and liver. Our results suggest that in non-diabetic, there is an inverse relationship between bone mineral density in lumbar spine and BMAT and a trend persists after adjustment for weight, age, BMI and height. While there is a positive association between visceral adipose tissue and intrahepatic lipids with serum insulin levels, there is no association between BMAT and serum levels of insulin. Conversely, a positive relationship was observed between BMAT and serum glucose levels, whereas this association was not observed with other fat deposits. These relationships did not apply after adjustment for body weight, BMI, height and age. The present study shows that in a group of predominantly non-obese women the association between insulin resistance and BMAT is not an early event, as occurs with visceral adipose tissue and intrahepatic lipids. On the other hand, BMAT has a negative relationship with bone mineral density. Taken together, the results support the view that bone has a complex and non-linear relationship with energy metabolism.
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Tecido Adiposo/anatomia & histologia , Densidade Óssea , Osso e Ossos/anatomia & histologia , Resistência à Insulina , Vértebras Lombares/anatomia & histologia , Absorciometria de Fóton , Adulto , Idoso , Peso Corporal , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Differently from most hormones, which commonly are specialized molecules able to influence other cells, tissues and systems, thyroid hormones (TH) are pleiotropic peptides, whose primordial function is difficult to identify. The complex action of TH on human economy can be easily witnessed by examining the diverse consequences of TH excess and deficiency during development and after maturity. In particular, different manifestations in bone modeling and remodeling reflect the circumstantial consequences of thyroid disturbances, which are age dependent. While hyperthyroidism during childhood enhances bone mineralization and accelerates epiphyseal maturation, in adults it induces bone loss by predominant activation of osteoclast activity. Furthermore, the syndrome of TH resistance is a multifaceted condition in which different sites exhibit signs of hormone excess or deficiency depending on the configuration of the TH receptor isoform. The investigation of the impact of TH resistance on the skeleton still remains to be elucidated. We present here a thorough review of the action of TH on bone and of the impact of thyroid disorders, including hyper- and hypothyroidism and the syndrome of TH resistance, on the skeleton.
Diferentemente da maioria dos hormônios, que usualmente são moléculas especializadas capazes de influenciar outras células, tecidos e sistemas, os hormônios da tireoide (HT) são peptídeos pleiotrópicos, cuja função primordial é difícil de identificar. A ação complexa dos HT na fisiologia humana pode ser facilmente reconhecida ao observar as diversas consequências do excesso e da deficiência de HT durante e após o pleno desenvolvimento. Em particular as diferentes manifestações na modelação e remodelação óssea refletem que as consequências esqueléticas das disfunções tireoidianas dependem das circunstâncias e variam com a idade. Enquanto o hipertireoidismo durante a infância aumenta a mineralização óssea e acelera a maturação epifisária, em adultos induz a perda óssea pela ativação predominante da ação osteoclástica. Além disso, a síndrome de resistência ao HT é uma condição multifacetada na qual diferentes tecidos apresentam sinais de excesso ou deficiência hormonal, dependendo da predominância da expressão das diversas isoformas do receptor de HT. O impacto da resistência ao HT sobre o esqueleto ainda é motivo de investigação. Apresentamos aqui uma revisão abrangente sobre as ações ósseas dos HT e o impacto no esqueleto dos distúrbios da tireoide, incluindo hipo e hipertireoidismo e síndrome de resistência ao HT.
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Animais , Humanos , Osso e Ossos/metabolismo , Hipotireoidismo/metabolismo , Minerais/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Tireotoxicose/metabolismo , Calcificação Fisiológica/fisiologia , Cálcio/metabolismo , Bases de Dados Bibliográficas , Epífises/crescimento & desenvolvimento , Osteoclastos/metabolismo , Osteoporose/etiologia , Fósforo/metabolismo , Doenças da Glândula Tireoide/metabolismo , Tireotoxicose/complicações , Tiroxina/metabolismo , Tri-Iodotironina/metabolismoRESUMO
BACKGROUND: The majority of Osteogenesis Imperfecta (OI) cases are caused by mutations in one of the two genes, COL1A1 and COL1A2 encoding for the two chains that trimerize to form the procollagen 1 molecule. However, alterations in gene expression and microRNAs (miRNAs) are responsible for the regulation of cell fate determination and may be evolved in OI phenotype. METHODS: In this work, we analyzed the coding region and intron/exon boundaries of COL1A1 and COL1A2 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. COL1A1 and miR-29b expression were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System. RESULTS: We have identified eight novel mutations, where of four may be responsible for OI phenotype. COL1A1 and miR-29b showed lower expression values in OI type I and type III samples. Interestingly, one type III OI sample from a patient with Bruck Syndrome showed COL1A1 and miR-29b expressions alike those from normal samples. CONCLUSIONS: Results suggest that the miR-29b mechanism directed to regulate collagen protein accumulation during mineralization is dependent upon the amount of COL1A1 mRNA. Taken together, results indicate that the lower levels observed in OI samples were not sufficient for the induction of miR-29b.
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Diferenciação Celular/genética , Colágeno Tipo I/genética , Expressão Gênica , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Osteoblastos/metabolismo , Osteogênese Imperfeita/genética , Adolescente , Adulto , Cadeia alfa 1 do Colágeno Tipo I , Éxons , Feminino , Ordem dos Genes , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Osteogênese Imperfeita/diagnóstico , Adulto JovemRESUMO
The GH/IGF-I axis has essential roles in regulating bone and vascular status. The age-related decrease in GH secretion ("somatopause") may contribute to osteoporosis and atherosclerosis, commonly observed in the elderly. Adult-onset GH deficiency (GHD) has been reported to be associated with reduced bone mineral density (BMD), increased risk of fractures, and premature atherosclerosis. We have shown the young adult individuals with isolated GHD (IGHD) due to a homozygous for the c.57+1G>A GHRH receptor gene mutation have normal volumetric BMD (vBMD), and not develop premature atherosclerosis, despite adverse risk factor profile. However, the bone and vascular impact of lifetime GHD on the aging process remains unknown. We studied a group of ten older IGHD subjects (≥60 years) homozygous for the mutation, comparing them with 20 age- and gender-matched controls (CO). Areal BMD was measured, and vBMD was calculated at the lumbar spine and total hip. Vertebral fractures and abdominal aortic calcifications (expressed as calcium score) were also assessed. Areal BMD was lower in IGHD, but vBMD was similar in the two groups. The percent of fractured individuals was similar, but the mean number of fractures per individual was lower in IGHD than CO. Calcium score was similar in the two groups. A positive correlation was found between calcium score and number of fractures. Untreated lifetime IGHD has beneficial consequences on bone status and does not have a deleterious effect on abdominal aorta calcification.
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Envelhecimento/fisiologia , Doenças da Aorta/epidemiologia , Densidade Óssea , Nanismo Hipofisário/epidemiologia , Calcificação Vascular/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/patologia , Estudos de Casos e Controles , Nanismo Hipofisário/genética , Feminino , Nível de Saúde , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Fraturas da Coluna Vertebral/epidemiologia , Coluna VertebralRESUMO
Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.
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Vitamin D an ancient secosteroid is essential for mineral homeostasis, bone remodeling, immune modulation, and energy metabolism. Recently, debates have emerged about the daily vitamin D requirements for healthy and elderly adults, the safety and efficacy of long term supplementation and the role of vitamin D deficiency in several chronic disease states. Since this molecule acts as both a vitamin and a hormone, it should not be surprising that the effects of supplementation are multi-faceted and complex. Yet despite significant progress in the last decade, our understanding of vitamin D physiology and the clinical relevance of low circulating levels of this vitamin remains incomplete. The present review provides the reader with a comprehensive and up-to-date understanding of vitamin D requirements and safety. It also raises some provocative research questions.
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Vitamina D/efeitos adversos , Vitamina D/metabolismo , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Estações do Ano , Pigmentação da Pele/efeitos da radiação , Luz Solar , Vitamina D/sangue , Deficiência de Vitamina D/metabolismoRESUMO
OBJECTIVE: Growth hormone (GH)/insulin-like growth factor (IGF) axis and insulin are key determinants of bone remodelling. Homozygous mutations in the GH-releasing hormone receptor (GHRHR) gene (GHRHR) are a frequent cause of genetic isolated GH deficiency (IGHD). Heterozygosity for GHRHR mutation causes changes in body composition and possibly an increase in insulin sensitivity, but its effects on bone quality are still unknown. The objective of this study was to assess the bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for a null mutation in the GHRHR. PATIENTS AND METHODS: A cross-sectional study was performed on 76 normal subjects (68·4% females) (N/N) and 64 individuals (64·1% females) heterozygous for a mutation in the GHRHR (MUT/N). Anthropometric features, quantitative ultrasound (QUS) of the heel, bone markers [osteocalcin (OC) and CrossLaps], IGF-I, glucose and insulin were measured, and homeostasis model assessment of insulin resistance (HOMA(IR) ) was calculated. RESULTS: There were no differences in age or height between the two groups, but weight (P = 0·007) and BMI (P = 0·001) were lower in MUT/N. There were no differences in serum levels of IGF-I, glucose, T-score or absolute values of stiffness and OC, but insulin (P = 0·01), HOMA(IR) (P = 0·01) and CrossLaps (P = 0·01) were lower in MUT/N. There was no correlation between OC and glucose, OC and HOMA(IR) in the 140 individuals as a whole or in the separate MUT/N or N/N groups. CONCLUSIONS: This study suggests that one allele mutation in the GHRHR gene has a greater impact on energy metabolism than on bone quality.
Assuntos
Remodelação Óssea/genética , Haploinsuficiência , Resistência à Insulina/genética , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Densidade Óssea/genética , Remodelação Óssea/fisiologia , Brasil , Estudos de Casos e Controles , Estudos Transversais , Feminino , Hormônio do Crescimento/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Osteocalcina/sangue , Receptores de Neuropeptídeos/deficiência , Receptores de Hormônios Reguladores de Hormônio Hipofisário/deficiênciaRESUMO
BACKGROUND: Rat tail suspension is an accepted method to create experimental osteopenia. However, suspension periods longer than 3 wk may cause tail skin sloughing or rat slippage. The hypothesis was that a traction system with skeletal anchorage through one tail vertebra would prolong the suspension time without significant complications. METHODS: There were 80 young adult female Wistar rats that were submitted to one of the following interventions: skeletal tail suspension (N = 20), skin tail suspension (N = 20), no intervention (N = 20), and a baseline control (N = 20). All animals were followed up either for 3 (N = 10) or 6 (N = 10) wk. Animals were assessed for clinical signs of stress and tolerance to suspension. The femur evaluation was in terms of mineral density content, mechanical resistance, and histomorphometry. RESULTS/DISCUSSION: All animals reached the 3-wk end point. However, for the 6-wk period, seven animals suspended by the skin traction method were discarded (70%) because of signs of stress and skin sloughing. In contrast, there was one loss in the skeletal suspension group (10%). All suspended animals developed similar osteopenia at 3 wk characterized by decreased bone mineral content, weakened bone resistance, and loss of femoral mass. At 6 wk, all suspended animals had similar osteopenic parameters, but they were not statistically different from those of the rats in the 3-wk groups. Therefore, suspension longer than 3 wk did not increase the bone deterioration in the femur.
Assuntos
Doenças Ósseas Metabólicas/etiologia , Elevação dos Membros Posteriores/métodos , Análise de Variância , Animais , Densidade Óssea , Feminino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The pathophysiology of hepatic osteodystrophy (HO) remains poorly understood. Our aim was to evaluate bone histomorphometry, biomechanical properties, and the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) system in the onset of this disorder. Forty-six male Wistar rats were divided into two groups: sham-operated (SO, n = 23) and bile duct-ligated (BDL, n = 23). Rats were killed on day 30 postoperatively. Immunohistochemical expression of IGF-I and GH receptor was determined in liver tissue and in the proximal growth plate cartilage of the left tibia. Histomorphometric analysis was performed in the right tibia, and the right femur was used for biomechanical analysis. The maximal force at fracture and the stiffness of the mid-shaft femur were, respectively, 53% and 24% lower in BDL compared to SO. Histomorphometric measurements showed low cancellous bone volume and decreased cancellous bone connectivity in BDL, compatible with osteoporosis. This group also showed increased mineralization lag time, indicating disturbance in bone mineralization. Serum levels of IGF-I were lower in BDL (basal 1,816 +/- 336 vs. 30 days 1,062 +/- 191 ng/ml, P < 0.0001). BDL also showed higher IGF-I expression in the liver tissue but lower IGF-I and GH receptor expression in growth plate cartilage than SO. Osteoporosis is the most important feature of HO; BDL rats show striking signs of reduced bone volume and decreased bone strength, as early as after 1 month of cholestasis. The endocrine and autocrine-paracrine IGF-I systems are deeply affected by cholestasis. Further studies will be necessary to establish their role in the pathogenesis of HO.
Assuntos
Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/patologia , Colestase Extra-Hepática/complicações , Hepatopatias/etiologia , Hepatopatias/patologia , Animais , Colestase Extra-Hepática/metabolismo , Modelos Animais de Doenças , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Wistar , Tíbia/metabolismo , Tíbia/patologiaRESUMO
The effects of 2 diets with different protein contents on weight loss and subsequent maintenance was assessed in obese cats. The control group [Co; n = 8; body condition score (BCS) = 8.6 +/- 0.2] received a diet containing 21.4 g crude protein (CP)/MJ of metabolizable energy and the high-protein group (HP; n = 7; BCS = 8.6 +/- 0.2) received a diet containing 28.4 g CP/MJ until the cats achieved a 20% controlled weight loss (0.92 +/- 0.2%/wk). After the weight loss, the cats were all fed a diet containing 28.0 g CP/MJ at an amount sufficient to maintain a constant body weight (MAIN) for 120 d. During weight loss, there was a reduction of lean mass in Co (P < 0.01) but not in HP cats and a reduction in leptinemia in both groups (P < 0.01). Energy intake per kilogram of metabolic weight (kg(-0.40)) to maintain the same rate of weight loss was lower (P < 0.04) in the Co (344 +/- 15.9 kJ x kg(-0.40) x d(-1)) than in the HP group (377 +/- 12.4 kJ. x kg(-0.40) x d(-1)). During the first 40 d of MAIN, the energy requirement for weight maintenance was 398.7 +/- 9.7 kJ.kg(-0.40) x d(-1) for both groups, corresponding to 73% of the NRC recommendation. The required energy gradually increased in both groups (P < 0.05) but at a faster rate in HP; therefore, the energy consumption during the last 40 d of the MAIN was higher (P < 0.001) for the HP cats (533.8 +/- 7.4 kJ x kg(-0.40) x d(-1)) than for the control cats (462.3 +/- 9.6 kJ x kg(-0.40) x d(-1)). These findings suggest that HP diets allow a higher energy intake to weight loss in cats, reducing the intensity of energy restriction. Protein intake also seemed to have long-term effects so that weight maintenance required more energy after weight loss.