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1.
PLoS One ; 15(2): e0228962, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084166

RESUMO

ChronoMID-neural networks for temporally-varying, hence Chrono, Medical Imaging Data-makes the novel application of cross-modal convolutional neural networks (X-CNNs) to the medical domain. In this paper, we present multiple approaches for incorporating temporal information into X-CNNs and compare their performance in a case study on the classification of abnormal bone remodelling in mice. Previous work developing medical models has predominantly focused on either spatial or temporal aspects, but rarely both. Our models seek to unify these complementary sources of information and derive insights in a bottom-up, data-driven approach. As with many medical datasets, the case study herein exhibits deep rather than wide data; we apply various techniques, including extensive regularisation, to account for this. After training on a balanced set of approximately 70000 images, two of the models-those using difference maps from known reference points-outperformed a state-of-the-art convolutional neural network baseline by over 30pp (> 99% vs. 68.26%) on an unseen, balanced validation set comprising around 20000 images. These models are expected to perform well with sparse data sets based on both previous findings with X-CNNs and the representations of time used, which permit arbitrarily large and irregular gaps between data points. Our results highlight the importance of identifying a suitable description of time for a problem domain, as unsuitable descriptors may not only fail to improve a model, they may in fact confound it.


Assuntos
Remodelação Óssea/fisiologia , Imageamento Tridimensional/métodos , Aprendizado de Máquina/estatística & dados numéricos , Animais , Interpretação Estatística de Dados , Aprendizado Profundo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Redes Neurais de Computação , Análise Espaço-Temporal , Microtomografia por Raio-X/métodos
2.
Z Gerontol Geriatr ; 53(2): 163-170, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950363

RESUMO

Osteoporotic bones heal more slowly and ineffectively than normal bones. A combination of antibodies against sclerosing protein (Scl-Ab), and parathyroid hormone 1-34 (PTH 1-34) may improve healing. A standard osteoporotic rat model was established 12 weeks after bilateral ovarian resection (OVX). Bone defects were created in the right femora of 80 rats, which were randomly divided into 4 groups: control, Scl-Ab (25 mg/kg twice weekly), PTH (60 µg/kg of PTH 1-34 three times a week) and PTH plus Scl-Ab. After 12 weeks of treatment the rats were sacrificed and blood and the distal femora were harvested for biochemical evaluation, histology, microcomputed tomography and biomechanical testing. Compared to the control group, monotherapy and combination therapy with PTH and/or Scl-Ab promoted the formation of new bone, enhanced maximum femoral loading and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. The administration of PTH + Scl-Ab maximally enhanced bone defect healing. Combination treatment was better than either treatment alone, indicating a synergistic effect.


Assuntos
Anticorpos/administração & dosagem , Proteínas Morfogenéticas Ósseas/imunologia , Remodelação Óssea/fisiologia , Consolidação da Fratura/efeitos dos fármacos , Hormônio Paratireóideo/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Calo Ósseo/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Humanos , Ovariectomia , Hormônio Paratireóideo/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X/métodos
3.
Nat Commun ; 11(1): 332, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949165

RESUMO

Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). However, how these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Cell-lineage analysis using Cxcl12-creER mice reveals that quiescent Cxcl12-creER+ perisinusoidal BMSCs differentiate into cortical bone osteoblasts solely during regeneration. A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory. ß-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER+ BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration.


Assuntos
Regeneração Óssea/fisiologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Esqueleto/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Células da Medula Óssea/citologia , Regeneração Óssea/genética , Remodelação Óssea/fisiologia , Linhagem da Célula , Transdiferenciação Celular , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Osteoblastos , Osteogênese/genética , Células-Tronco , Tamoxifeno/farmacologia
4.
Rev. int. med. cienc. act. fis. deporte ; 19(76): 617-626, dic. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-187235

RESUMO

El objetivo de este estudio fue evaluar la densidad mineral ósea (DMO) y el contenido mineral óseo (CMO) de los segmentos corporales durante un periodo de entrenamiento de seis meses. Se evaluaron a 41 futbolistas juveniles profesionales en dos momentos, una al comienzo (TI) y otra al final (TF) de la intervención con el equipo de absorciometría dual de rayos X (DEXA). Se lograron aumentos significativos en la DMO en los segmentos corporales de la cadera, columna lumbar, triangulo de Ward, tronco y del cuerpo total (p<0.05). También se obtuvo un incremento significativo del CMO en la cadera, columna lumbar, pierna, tronco y costillas (p<0.05). El entrenamiento de futbol fortaleció el CMO y la DMO del hueso de la extremidad inferior y de la caja torácica, con lo cual el fútbol podría ser una actividad útil para la mejorar la mineralización y fortalecimiento del hueso, para prevenir lesiones y fracturas


The objective of this study was to assess bone mineral density (BMD) and bone mineral content (BMC) of body segments for a six months training period. 41 professional youth players were evaluated in two moments, one at the beginning (TI) and another at the end (TF) of the intervention with the dual energy x-ray absorptiometry equipment (DEXA). Significant increases in BMD were achieved in the body segments of the hip, lumbar spine, ward triangle, trunk and total body (p <0.05). There was also a significant increase in BMC in the hip, lumbar spine, leg, trunk and ribs (p <0.05). Soccer training strengthened the BMC and BMD of the lower limb bone and the rib cage, which could be a useful activity to improve bone mineralization and strengthening, to prevent injuries and fractures


Assuntos
Humanos , Masculino , Adolescente , Futebol/fisiologia , Densidade Óssea/fisiologia , Antropometria , Calcificação Fisiológica/fisiologia , Traumatismos em Atletas/prevenção & controle , Remodelação Óssea/fisiologia , Estudos Longitudinais , Absorciometria de Fóton/instrumentação
5.
Biomed Res Int ; 2019: 6712591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886238

RESUMO

Phosphatase and tensin homolog (PTEN) is a critical regulator of tumorigenesis and bone remodeling, which is also found expressed in the periodontal tissues. Periodontitis is one of the most common oral diseases and associated with alveolar bone resorption and tooth loosening in adults. However, the functional relevance of PTEN in periodontitis remains unclear. Here, we report that PTEN plays an essential role in periodontitis. The in vivo results of our study showed a significant decrease of PTEN in the ligature-induced mouse periodontitis model. The function of PTEN in the macrophages was shown to be associated with inflammatory factors interleukin 1 (IL1) and tumor necrosis factor (TNF-α) by using overexpression and silence methods. Further mechanistic studies indicated lack of PTEN-activated IL1 and TNF-α, which increased the number of osteoclasts and led to alveolar bone erosion and loss. Moreover, PTEN nanoparticles could directly inhibit the inflammatory process and bone erosion, suggesting a controlling role of PTEN during bone remodeling. All these data identified the novel function of PTEN as a key factor in periodontitis and bone remodeling.


Assuntos
Perda do Osso Alveolar/metabolismo , PTEN Fosfo-Hidrolase , Periodontite/metabolismo , Animais , Remodelação Óssea/fisiologia , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
J Appl Oral Sci ; 27: e20180596, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31508793

RESUMO

Bone development and healing processes involve a complex cascade of biological events requiring well-orchestrated synergism with bone cells, growth factors, and other trophic signaling molecules and cellular structures. Beyond health processes, MMPs play several key roles in the installation of heart and blood vessel related diseases and cancer, ranging from accelerating metastatic cells to ectopic vascular mineralization by smooth muscle cells in complementary manner. The tissue inhibitors of MMPs (TIMPs) have an important role in controlling proteolysis. Paired with the post-transcriptional efficiency of specific miRNAs, they modulate MMP performance. If druggable, these molecules are suggested to be a platform for development of "smart" medications and further clinical trials. Thus, considering the pleiotropic effect of MMPs on mammals, the purpose of this review is to update the role of those multifaceted proteases in mineralized tissues in health, such as bone, and pathophysiological disorders, such as ectopic vascular calcification and cancer.


Assuntos
Remodelação Óssea/fisiologia , Matriz Extracelular/fisiologia , Metaloproteinases da Matriz/fisiologia , Doenças Ósseas/metabolismo , Doenças Ósseas/fisiopatologia , Progressão da Doença , Humanos , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Osteoblastos/fisiologia , Inibidores Teciduais de Metaloproteinases/fisiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/fisiopatologia
7.
Comput Methods Biomech Biomed Engin ; 22(16): 1247-1257, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31497997

RESUMO

One of the major causes of implant loosening is due to excessive bone resorption surrounding the implant due to bone remodelling. The objective of the study is to investigate the effects of implant material and implant-bone interface conditions on bone remodelling around tibia bone due to total ankle replacement. Finite element models of intact and implanted ankles were developed using CT scan data sets. Bone remodelling algorithm was used in combination with FE analysis to predict the bone density changes around the ankle joint. Dorsiflexion, neutral, and plantar flexion positions were considered, along with muscle force and ligaments. Implant-bone interfacial conditions were assumed as debonded and bonded to represent non-osseointegration and fully osseointegration at the porous coated surface of the implant. To investigate the effect of implant material, three finite element models having different material combinations of the implant were developed. For model 1, tibial and talar components were made of Co-Cr-Mo, and meniscal bearing was made of UHMWPE. For model 2, tibial and talar components were made of ceramic and meniscal bearing was made of UHMWPE. For model 3, tibial and talar components were made of ceramic and meniscal bearing was made of CFR-PEEK. Changes in implant material showed no significant changes in bone density due to bone remodelling. Therefore, ceramic appears to be a viable alternative to metal and CFR-PEEK can be used in place of UHMWPE. This study also indicates that proper bonding between implant and bone is essential for long-term survival of the prosthetic components.


Assuntos
Artroplastia de Substituição do Tornozelo , Remodelação Óssea/fisiologia , Próteses e Implantes , Tíbia/fisiologia , Algoritmos , Densidade Óssea/fisiologia , Interface Osso-Implante/fisiologia , Cartilagem/fisiologia , Simulação por Computador , Análise de Elementos Finitos , Humanos , Osseointegração/fisiologia
8.
Eur J Endocrinol ; 181(5): 525-537, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536965

RESUMO

Objective: To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance. Design: Cross-sectional study. Methods: Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls. Results: Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling - ß catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load. Conclusions: Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.


Assuntos
Remodelação Óssea/fisiologia , Resistência à Insulina/fisiologia , MicroRNAs/sangue , RNA Mensageiro/sangue , Adulto , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Via de Sinalização Wnt/fisiologia
9.
Nat Commun ; 10(1): 3436, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366886

RESUMO

Mineralized bone forms when collagen-containing osteoid accrues mineral crystals. This is initiated rapidly (primary mineralization), and continues slowly (secondary mineralization) until bone is remodeled. The interconnected osteocyte network within the bone matrix differentiates from bone-forming osteoblasts; although osteoblast differentiation requires EphrinB2, osteocytes retain its expression. Here we report brittle bones in mice with osteocyte-targeted EphrinB2 deletion. This is not caused by low bone mass, but by defective bone material. While osteoid mineralization is initiated at normal rate, mineral accrual is accelerated, indicating that EphrinB2 in osteocytes limits mineral accumulation. No known regulators of mineralization are modified in the brittle cortical bone but a cluster of autophagy-associated genes are dysregulated. EphrinB2-deficient osteocytes displayed more autophagosomes in vivo and in vitro, and EphrinB2-Fc treatment suppresses autophagy in a RhoA-ROCK dependent manner. We conclude that secondary mineralization involves EphrinB2-RhoA-limited autophagy in osteocytes, and disruption leads to a bone fragility independent of bone mass.


Assuntos
Autofagia/fisiologia , Doenças do Desenvolvimento Ósseo/genética , Calcificação Fisiológica/fisiologia , Efrina-B2/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Autofagossomos/fisiologia , Autofagia/genética , Doenças do Desenvolvimento Ósseo/patologia , Remodelação Óssea/fisiologia , Linhagem Celular , Efrina-B2/genética , Camundongos , Camundongos Endogâmicos C57BL , Osteócitos/metabolismo , Osteócitos/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética
10.
Nat Rev Endocrinol ; 15(11): 651-665, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31462768

RESUMO

Osteoblasts are specialized mesenchymal cells that synthesize bone matrix and coordinate the mineralization of the skeleton. These cells work in harmony with osteoclasts, which resorb bone, in a continuous cycle that occurs throughout life. The unique function of osteoblasts requires substantial amounts of energy production, particularly during states of new bone formation and remodelling. Over the last 15 years, studies have shown that osteoblasts secrete endocrine factors that integrate the metabolic requirements of bone formation with global energy balance through the regulation of insulin production, feeding behaviour and adipose tissue metabolism. In this article, we summarize the current understanding of three osteoblast-derived metabolic hormones (osteocalcin, lipocalin and sclerostin) and the clinical evidence that suggests the relevance of these pathways in humans, while also discussing the necessity of specific energy substrates (glucose, fatty acids and amino acids) to fuel bone formation and promote osteoblast differentiation.


Assuntos
Remodelação Óssea/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Osteoblastos/fisiologia , Osteogênese/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Humanos , Lipocalinas/metabolismo , Osteocalcina/metabolismo
11.
Osteoporos Int ; 30(9): 1827-1836, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31309239

RESUMO

Treatment effects of combining teriparatide and whole-body vibration exercise (WBV) vs teriparatide alone in twelve months were compared using bone mineral density (BMD), bone microarchitecture, and bone turnover markers. We found an increased effect in lumbar spine BMD by adding WBV to teriparatide in postmenopausal osteoporotic women. INTRODUCTION: The parathyroid hormone (PTH) analogue teriparatide is an effective but expensive anabolic treatment for osteoporosis. Whole-body vibration exercise (WBV) has been found to stimulate muscle and bone strength in some studies. Animal data demonstrate a beneficial effect on bone when combining PTH with mechanical loading. The aim of this study was to investigate if combining WBV exercise and teriparatide treatment gives additional beneficial effects on bone compared to teriparatide alone in postmenopausal women with osteoporosis. METHODS: The PaVOS study is a randomized controlled trial where postmenopausal osteoporotic women starting teriparatide 20 µg/day were randomized to WBV + teriparatide or teriparatide alone. WBV consisted of three sessions a week (12 min, including 1:1 ratio of exercise:rest). Bone mineral density (BMD) and bone microarchitecture, bone turnover markers, and sclerostin measurements were obtained. Data were analyzed using a linear mixed regression model with adjustment for baseline values or robust cluster regression in an intention-to-treat (ITT) analysis. RESULTS: Thirty-five women were randomized (17 in teriparatide + WBV group and 18 in teriparatide group). At 12 months, both groups increased significantly in BMD at the lumbar spine. The teriparatide + WBV group increased by (mean ± SD) 8.90% ± 5.47 and the teriparatide group by 6.65% ± 5.51. The adjusted treatment effect of adding WBV to teriparatide was statistically significant at 2.95% [95% CI = 0.14-5.77; P = 0.040]. Markers of bone turnover increased significantly in both groups at three and six months with no significant difference between groups. No other treatment effects were observed in hip BMD, bone microarchitecture parameters, or sclerostin levels in either group. CONCLUSION: Twelve months of WBV and teriparatide had a significant clinically relevant treatment effect in lumbar spine BMD compared to teriparatide alone in postmenopausal osteoporotic women. ClinicalTrials.gov :(NCT02563353).


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Terapia por Exercício/métodos , Osteoporose Pós-Menopausa/terapia , Teriparatida/uso terapêutico , Vibração , Absorciometria de Fóton/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Terapia Combinada , Feminino , Articulação do Quadril/fisiopatologia , Humanos , Vértebras Lombares/fisiopatologia , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Tomografia Computadorizada por Raios X/métodos
12.
Acta Orthop ; 90(5): 479-483, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31269876

RESUMO

Background and purpose - Bone remodeling as a response to bone trauma, postoperative immobilization, and device-related bone reactions can lead to loss of bone stock and increase the risk of periprosthetic fracture and aseptic loosening. This study investigates the adaptive bone remodeling of the proximal tibia after uncemented total knee arthroplasty (TKA). Patients and methods - We performed a 2-year follow up of 53 patients (mean age 62 (38-70) years, 27 of whom were men, who received an uncemented TKA in a randomized controlled trial with bone mineral density (BMD) as secondary endpoint. Patients were randomized to 2 groups of either monoblock (A) or modular (B) polyethylene design. The TKAs were performed using the uncemented Zimmer Nexgen trabecular metal. Measurements of BMD were done postoperatively and after 3, 6, 12, and 24 months. BMD was measured in 3 regions of interest (ROI). Results and interpretation - In group A statistically significant changes in BMD were seen after 24 months in both the medial and lateral ROI. BMD decreased medially by 15% (p = 0.004) and laterally by 13% (p = 0.01). In group B the BMD changes were limited and after 24 months returned to the preoperative values. The differences in BMD change between groups were statistically significant in both the medial (p = 0.03) and lateral (p = 0.02) ROI. In the distal ROI we found no significant change in BMD in either group. A significantly different bone remodeling pattern of the proximal tibia was seen in the 2 groups with a higher degree of bone loss in the knees that received the monoblock polyethylene design, indicating that the flexible monoblock implant design, previously shown to improve fixation, does not decrease the bone loss of the proximal tibia.


Assuntos
Artroplastia do Joelho/métodos , Remodelação Óssea/fisiologia , Prótese do Joelho , Tíbia/fisiopatologia , Absorciometria de Fóton/métodos , Adulto , Idoso , Densidade Óssea/fisiologia , Cimentação , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/cirurgia , Desenho de Prótese , Tíbia/diagnóstico por imagem
13.
Medicina (B Aires) ; 79(3): 217-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284259

RESUMO

Hypovitaminosis D, defined by low serum levels of 25(OH)D, is a recognized worldwide public health problem. The most accepted definition considers that deficiency occurs with serum levels fall below 12 ng/ml of 25(OH)D. Long term vitamin D deficiency results in decreased bone mineralization, secondary hyperparathyroidism, increased cortical bone loss (pathogenesis of osteoporosis and hip fractures), differentiation and division of various cell types, muscle strength, diabetes type 2, blood pressure, etc. Twin- and family-based studies indicate that genetic factors influence serum 25(OH)D levels. Genetic studies have shown single-nucleotide polymorphisms (SNPs) are linked to low serum 25(OH)D concentrations through changes in the activity of the enzymes of the 1a,25(OH)2D metabolic pathway. Carriers of high genetic risk scores would need a h igher amount of vitamin D supplementation to achieve adequate serum 25(OH)D concentrations. Clinicians would not need to indicate studies to identify patients with vitamin D insufficiency of genetic origin. They should instruct their patients on their own care, to control the intake of vitamin D and the serum 25(OH)D levels until the latter are adequate. Overall, the literature reveals that the consequences of hypovitaminosis D on bone health are observed in old and infrequently in young subjects. A probable explanation for the latter is: if the rate of bone remodeling allows it, bone tissue has endogenous (genetics, hormones) and exogenous determinants (diet, physical activity) that may compensate the variables of bone health. The consequences of vitamin D deficit on bone health, has not been completely uncovered.


Assuntos
Remodelação Óssea/genética , Deficiência de Vitamina D/genética , Remodelação Óssea/fisiologia , Feminino , Humanos , Masculino , Hormônio Paratireóideo/sangue , Polimorfismo de Nucleotídeo Único , Deficiência de Vitamina D/sangue
14.
Life Sci ; 231: 116556, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194990

RESUMO

Triiodothyronine (T3) and estrogen (E2) play important roles in the bone remodeling process and signaling of receptor activator of the nuclear factor-kappa ß (RANKL) and osteoprotegerin (OPG) expressed by osteoblasts. However, little is known of the molecular action of these hormones in conditions of hyperthyroidism and associated E2 in human cells. AIMS: This study evaluated the effects of the physiological concentration of E2 (10 nM), alone or in association with physiological (1 nM) and supraphysiological (10 nM) concentrations of T3, on RANKL and OPG gene expression in human osteoblasts. MAIN METHODS: Alkaline phosphatase and osteocalcin assays were performed to verify the presence of mature osteoblasts. After mimicking the experimental hyperthyroidism in osteoblasts untreated or treated with E2, RANKL and OPG gene expression was analyzed by real-time PCR and protein expression by western Blot and ELISA. Alizarin Red staining analyzed the amount of bone matrix after hormonal treatments. KEY FINDINGS: E2 enhanced the gene expression of OPG when associated with 1 nM and 10 nM T3. E2 was able to restore the bone matrix after an initial decrease using 1 nM and 10 nM T3. The protective effect of E2 on the RANKL and OPG signaling pathway was demonstrated. E2 restored the bone matrix induced by experimental hyperthyroidism. SIGNIFICANCE: The data highlight the importance of E2 to maintain OPG expression and osteoblast activity against possible loss of bone mass, especially in conditions where T3 is in excess.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Estrogênios/fisiologia , Osteoblastos/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Remodelação Óssea/fisiologia , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Estrogênios/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertireoidismo/metabolismo , Células-Tronco Mesenquimais/fisiologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina/fisiologia
15.
Eur J Endocrinol ; 181(3): 221-231, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31189129

RESUMO

Objective: Bone turnover has a diurnal variation influenced by food intake, incretin hormones, the sympathetic nervous system and osteocyte function. The aim of the study was to compare diurnal variation in bone turnover in patients with diabetes and controls. Design: A clinical 24-h study with patients with type 1 diabetes (n = 5), patients with type 2 diabetes (n = 5) and controls (n = 5). Methods: Inclusion criterion: age >50 years. Exclusion criteria: diseases/medication that affect bone metabolism or recent use of incretin-based drugs. We drew blood samples hourly during the day and every 3 h during the night. We served an identical diet on all study days. We used repeated-measures one-way ANOVA to compare the levels of the investigated markers, and we quantified the effect of time by comparing group mean standard deviations. Results: The bone formation marker procollagen type 1 N-terminal propeptide showed a significant interaction between time and group (P = 0.01), and the mean standard deviation was lower in patients with type 2 diabetes compared with controls (P = 0.04) and patients with type 1 diabetes (P = 0.02). Other markers of bone formation and resorption showed significant effect of time. Levels of glucagon-like peptide-2, glucose-dependent insulinotropic peptide and sclerostin only showed significant effect of time (all P values 0.01), but levels of sclerostin tended to being highest in type 2 diabetes and lowest in controls. Conclusions: The diurnal variation in bone formation is attenuated in patients with type 2 diabetes. This is not explained by changes in incretin hormone levels, but possibly mediated by sclerostin.


Assuntos
Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Osteogênese/fisiologia , Idoso , Remodelação Óssea/fisiologia , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Osteoporos Int ; 30(9): 1755-1765, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227885

RESUMO

The relationships of osteocalcin (OC) and C-telopeptide of type I collagen (CTX) with long-term incidence of hip fracture were examined in 1680 post-menopausal women from a population-based study. CTX, but not OC, levels were associated with incident hip fracture in these participants, a relationship characterized by an inverted U-shape. INTRODUCTION: We sought to investigate the relationships of OC, a marker of bone formation, and CTX, a marker of bone resorption, with long-term incidence of hip fracture in older women. METHODS: We included 1680 women from the population-based Cardiovascular Health Study (mean [SD] age 74.5 [5.0] years). The longitudinal association of both markers with incidence of hip fracture was examined using multivariable Cox models. RESULTS: During a median follow-up of 12.3 years, 288 incident hip fractures occurred. Linear spline analysis did not demonstrate an association between OC levels and incident hip fracture. By contrast, increasing levels of CTX up to the middle-upper range were associated with a significantly greater risk of hip fracture (HR = 1.52 per SD increment, 95% CI = 1.10-2.09), while further increases were associated with a marginally non-significant lower risk (HR = 0.80 per SD increment, 95% CI = 0.63-1.01), after full adjustment for potential confounders. In analyses of quartiles, CTX exhibited a similar inverted U-shaped relationship with incident fracture after adjustment, with a significant association observed only for the comparison of quartile 3 to quartile 1 (HR = 1.63, 95% CI = 1.10-2.43). In a subset with available measures, both OC and CTX were inversely associated with bone mineral density of the hip. CONCLUSION: CTX, but not OC, levels were associated with incident hip fracture in post-menopausal women, a relationship characterized by an inverted U-shape. These findings highlight the complex relationship of bone turnover markers with hip fracture risk.


Assuntos
Remodelação Óssea/fisiologia , Fraturas do Quadril/fisiopatologia , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Densidade Óssea/fisiologia , Colágeno Tipo I/sangue , Feminino , Seguimentos , Fraturas do Quadril/sangue , Fraturas do Quadril/epidemiologia , Humanos , Incidência , Estilo de Vida , Osteocalcina/sangue , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/epidemiologia , Fraturas por Osteoporose/sangue , Fraturas por Osteoporose/epidemiologia , Peptídeos/sangue , Desempenho Físico Funcional , Medição de Risco/métodos , Estados Unidos/epidemiologia
17.
Forensic Sci Int ; 302: 109856, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247451

RESUMO

The assessment and interpretation of the timing of skeletal trauma can be of extreme difficulty in post-mortem specimens, especially because of post-mortem processes and taphonomic events. The chronological diagnosis of bone trauma, consisting usually in the gross distinction between antemortem, perimortem and post-mortem, is based almost uniquely on macroscopic and morphologic parameters in the anthropological field. However, both the interference of taphonomy and the scarce persistence of specific features indicating vitality (meaning etymologically "produced in life") and/or some very early bone healing reactions, make it extremely difficult. In this perspective, it is important not only to distinguish between peri and post-mortem lesions, but also to interpret perimortem lesions with respect to vitality and time elapsed since the trauma which may change the course of the investigations. And techniques of forensic pathology applied to forensic anthropology can come in extremely handy. If any traces of vital blood extravasation, haemorrhage, hematoma, inflammation, and biomarkers of early healing reaction are found in the bone tissue of a skeletal lesion (regardless the state of preservation of the body), then can they be used as a diagnostic tool or marker of vitality for that lesion? In these terms, vital reactions like bleeding or any early sign of bone healing can be the only evidence for demonstrating that a traumatic event was prior the death. Nevertheless, very little information, or research for that matter, is available in literature concerning persistence and detectability of vitality markers during the bone decomposition process. A fundamental point for properly determining the vitality of a fracture and estimating the post-traumatic time interval in skeletal lesions is the physio-pathological picture of the very initial healing process. This article attempts to provide a review of the physiopathological current knowledge available and applicable to osteology.


Assuntos
Remodelação Óssea/fisiologia , Fraturas Ósseas/patologia , Osteogênese/fisiologia , Biomarcadores/metabolismo , Coagulação Sanguínea/fisiologia , Citocinas/fisiologia , Hematoma/patologia , Hemorragia/patologia , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neovascularização Fisiológica/fisiologia , Osteoblastos/fisiologia , Osteoclastos/fisiologia
18.
Biomech Model Mechanobiol ; 18(5): 1475-1496, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31087221

RESUMO

Significant progress has been made to identify the cells and signaling molecules involved in the mechanobiological regulation of bone remodeling. It is now well accepted that osteocytes act as mechanosensory cells in bone expressing several signaling molecules such as nitric oxide (NO) and sclerostin (Scl) which are able to control bone remodeling responses. In this paper, we present a comprehensive multiscale computational model of bone remodeling which incorporates biochemical osteocyte feedback. The mechanostat theory is quantitatively incorporated into the model using mechanical feedback to control expression levels of NO and Scl. The catabolic signaling pathway RANK-RANKL-OPG is co-regulated via (continuous) PTH and NO, while the anabolic Wnt signaling pathway is described via competitive binding reactions between Wnt, Scl and the Wnt receptors LRP5/6. Using this novel model of bone remodeling, we investigate the effects of changes in the mechanical loading and hormonal environment on bone balance. Our numerical simulations show that we can calibrate the mechanostat anabolic and catabolic regulatory mechanisms so that they are mutually exclusive. This is consistent with previous models that use a Wolff-type law to regulate bone resorption and formation separately. Furthermore, mechanical feedback provides an effective mechanism to obtain physiological bone loss responses due to mechanical disuse and/or osteoporosis.


Assuntos
Osso e Ossos/fisiologia , Simulação por Computador , Retroalimentação , Modelos Biológicos , Osteócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/sangue , Apoptose , Ligação Competitiva , Fenômenos Biomecânicos , Remodelação Óssea/fisiologia , Diferenciação Celular , Proliferação de Células , Feminino , Humanos , Ligantes , Óxido Nítrico/metabolismo , Osteócitos/citologia , Hormônio Paratireóideo/metabolismo , Proteólise , Ligante RANK/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
19.
Seizure ; 69: 186-192, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075750

RESUMO

PURPOSE: The effects of antiseizure medications (ASMs) on bone metabolism is inconsistent. Most studies are in high income settings and none from sub-Saharan Africa. METHODS: A hospital based cross-sectional study in a paediatric epilepsy service with a comparison group assessed vitamin D metabolism. RESULTS: Seventy-five children with epilepsy and 75 comparison group were recruited. Median age for children with epilepsy was 9 years (range 1-17 years) and controls 3 years (range 1-12 years). Vitamin D deficiency occurred in 11(16.2%) children with epilepsy versus 6 (8.8%) control group (p = 0.29). Vitamin D insufficiency occurred in 30 (44.1%) children with epilepsy compared to 27(39.7%) control group. Children on ASMs had lower mean vitamin D levels than the control group (p = 0.02). Children on enzyme-inducing ASMs had lower mean vitamin D levels (p = 0.08), vitaminD2 (p = 0.0018), vitaminD3 (p = 0.004), serum phosphate levels (p = 0.000), and higher mean parathyroid hormone levels (p = 0.03) compared to controls. There was no difference in dietary intake and ancestry, although the dietary content of both groups was low in vitamin D products. CONCLUSIONS: Low vitamin D levels were common in children from both groups, but statistically lower for the children on ASMs. Children on enzyme-inducing ASMs need screening for vitamin D deficiency. The literature supports extending this for all children on ASMs. This is the first study to report that children on enzyme-inducing ASMs have lower levels of Vitamin D2 and D3 levels, probably as result of increased destruction of vitamin D. Improved vitamin D intake for children in vulnerable settings is important.


Assuntos
Remodelação Óssea , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Vitamina D/metabolismo , Adolescente , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Dieta , Epilepsia/complicações , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , África do Sul/epidemiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/metabolismo
20.
Int Rev Cell Mol Biol ; 346: 97-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31122396

RESUMO

Historically, cellular senescence has been viewed as an irreversible cell-cycle arrest process with distinctive phenotypic alterations that were implicated primarily in aging and tumor suppression. Recent discoveries suggest that cellular senescence represents a series of diverse, dynamic, and heterogeneous cellular states with the senescence-associated secretory phenotype (SASP). Although senescent cells typically contribute to aging and age-related diseases, accumulating evidence has shown that they also have important physiological functions during embryonic development, late pubertal bone growth cessation, and adulthood tissue remodeling. Here, we review the recent research on cellular senescence and SASP, highlighting the key pathways that mediate senescence cell-cycle arrest and initiate SASP. We also summarize recent literature on the role of cellular senescence in maintaining bone homeostasis and mediating age-associated osteoporosis, discussing both the beneficial and adverse roles of cellular senescence in bone during different physiological stages, including bone development, childhood bone growth, adulthood bone remodeling, and bone aging.


Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/embriologia , Osso e Ossos/fisiologia , Senescência Celular/fisiologia , Animais , Doenças Ósseas/patologia , Doenças Ósseas/fisiopatologia , Remodelação Óssea/fisiologia , Humanos
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