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1.
J Steroid Biochem Mol Biol ; 199: 105606, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31981800

RESUMO

In 2016, the Multiple Sclerosis (MS) Society of Canada convened a panel of expert scientists, clinicians and patient advocate to review the evidence for an association between vitamin D status and MS prevention and/or disease modification. The goal was to develop clear and accurate recommendations on optimal vitamin D intake and status for people affected by MS for use in clinical practice and public health policy. The final consensus report was based on a review and grading of existing published papers combined with expert opinions of panel members. The report led to recommendations published in November of 2018 on the website of the MS Society of Canada, one in a format for use by health professionals and another in a question and answer format that was targeted to persons affected by MS and the general public. For people at risk of developing MS, the vitamin D recommendations are similar to those for the general public following the Dietary Reference Intakes (DRI) for Canada and the United States. Adults should achieve and maintain a normal vitamin D status with monitoring by physicians (serum 25-hydroxyvitamin D (25(OH)D) = 50-125 nmol/L, requiring 600-4000 IU vitamin D/d intake). For pregnant women, newborn infants, and all youth at risk of MS, vitamin D intakes should also follow DRI recommendations but additionally their serum 25-(OH)D should be monitored. For persons living with MS, existing evidence did not allow prediction of a vitamin D intake that might modify MS disease course. For this group the recommendations included: (1) serum 25-(OH)D should be maintained in the range of 50-125 nmol/L (600-4000 IU/d intake).; and (2) vitamin D should not be used as a standalone treatment for MS. For children and adolescents, serum 25OHD status was recommended to be measured upon diagnosis of a first clinical demyelinating event, and monitored every 6 months to achieve a target of 75 nmol/L Since people living with MS are at increased risk of osteoporosis, falls, and bone fractures, it was recommended to achieve a minimum serum 25OHD concentration that is protective for bone health in the general population. The revision of the MS Society recommendations on vitamin D awaits future clinical trial evidence.


Assuntos
Esclerose Múltipla/dietoterapia , Osteoporose/dietoterapia , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Adulto , Densidade Óssea/efeitos dos fármacos , Calcifediol/efeitos adversos , Calcifediol/uso terapêutico , Canadá/epidemiologia , Criança , Suplementos Nutricionais , Feminino , Fraturas Ósseas/dietoterapia , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Humanos , Lactente , Recém-Nascido , Esclerose Múltipla/sangue , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Estado Nutricional , Osteoporose/metabolismo , Gravidez , Vitamina D/efeitos adversos , Vitamina D/sangue , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/patologia
2.
Sci Rep ; 10(1): 254, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937885

RESUMO

The recent discovery of bone flexoelectricity (strain-gradient-induced electrical polarization) suggests that flexoelectricity could have physiological effects in bones, and specifically near bone fractures, where flexoelectricity is theoretically highest. Here, we report a cytological study of the interaction between crack stress and bone cells. We have cultured MC3T3-E1 mouse osteoblastic cells in biomimetic microcracked hydroxyapatite substrates, differentiated into osteocytes and applied a strain gradient to the samples. The results show a strong apoptotic cellular response, whereby mechanical stimulation causes those cells near the crack to die, as indicated by live-dead and caspase staining. In addition, analysis two weeks post-stimulation shows increased cell attachment and mineralization around microcracks and a higher expression of osteocalcin -an osteogenic protein known to be promoted by physical exercise. The results are consistent with flexoelectricity playing at least two different roles in bone remodelling: apoptotic trigger of the repair protocol, and electro-stimulant of the bone-building activity of osteoblasts.


Assuntos
Fraturas Ósseas/patologia , Células 3T3 , Animais , Apoptose , Impedância Elétrica , Fraturas Ósseas/metabolismo , Camundongos , Minerais/metabolismo , Modelos Biológicos , Osteócitos/metabolismo , Osteócitos/patologia , Estresse Mecânico
3.
Nat Rev Endocrinol ; 16(2): 91-103, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792439

RESUMO

Osteoporosis is a highly prevalent disorder characterized by low bone mineral density and an increased risk of fracture, termed osteoporotic fracture. Notably, bone mineral density, osteoporosis and osteoporotic fracture are highly heritable; however, determining the genetic architecture, and especially the underlying genomic and molecular mechanisms, of osteoporosis in vivo in humans is still challenging. In addition to susceptibility loci identified in genome-wide association studies, advances in various omics technologies, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, have all been applied to dissect the pathogenesis of osteoporosis. However, each technology individually cannot capture the entire view of the disease pathology and thus fails to comprehensively identify the underlying pathological molecular mechanisms, especially the regulatory and signalling mechanisms. A change to the status quo calls for integrative multi-omics and inter-omics analyses with approaches in 'systems genetics and genomics'. In this Review, we highlight findings from genome-wide association studies and studies using various omics technologies individually to identify mechanisms of osteoporosis. Furthermore, we summarize current studies of data integration to understand, diagnose and inform the treatment of osteoporosis. The integration of multiple technologies will provide a road map to illuminate the complex pathogenesis of osteoporosis, especially from molecular functional aspects, in vivo in humans.


Assuntos
Densidade Óssea/fisiologia , Estudo de Associação Genômica Ampla/métodos , Osteoporose/genética , Osteoporose/metabolismo , Epigenômica/métodos , Fraturas Ósseas/genética , Fraturas Ósseas/metabolismo , Fraturas Ósseas/prevenção & controle , Genômica/métodos , Humanos , Metabolômica/métodos , Osteoporose/epidemiologia , Proteômica/métodos
4.
J Orthop Res ; 38(4): 695-707, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31729041

RESUMO

Impaired fracture healing continues to be a significant public health issue. This is more frequently observed in aging populations and patients with co-morbidities that can directly influence bone repair. Tremendous progress has been made in the development of biologics to enhance and accelerate the healing process; however, side-effects persist that can cause significant discomfort and tissue damage. This has been the impetus for the development of safe and natural strategies to hasten natural bone healing. Of the many possible approaches, nutrition represents a safe, affordable, and non-invasive strategy to positively influence each phase of fracture repair. However, our understanding of how healing can be hindered by malnutrition or enhanced with nutritional supplementation has lagged behind the advancements in both surgical management and the knowledge of molecular and cellular drivers of skeletal fracture repair. This review serves to bridge this knowledge gap as well as define the importance of nutrition during fracture healing. The extant literature clearly indicates that pre-existing nutritional deficiencies should be corrected, and nutritional status should be carefully monitored to prevent the development of malnutrition for the best possible healing outcome. It remains unclear, however, whether the provision of nutrients beyond sufficiency has any benefit on fracture repair and patient outcomes. The combined body of pre-clinical studies using a variety of animal models suggests a promising role of nutrition as an adjuvant therapy to facilitate fracture repair, but extensive research is needed, specifically at the clinical level, to clarify the utility of nutritional interventions in orthopedics. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:695-707, 2020.


Assuntos
Suplementos Nutricionais , Consolidação da Fratura , Fraturas Ósseas/metabolismo , Desnutrição/metabolismo , Animais , Humanos , Desnutrição/dietoterapia
5.
Proc Inst Mech Eng H ; 234(1): 74-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31702442

RESUMO

For radial head osteosynthesis, biodegradable implants are gaining in importance to minimize cartilage destruction and implant impingement and to supersede implant removal. Since loss of reduction and pseudarthrosis remain challenging complications, new implants should at least provide comparable biomechanical properties as commonly used metal implants. The objective of this study was to compare the treatment by polylactide pins to titanium screws and to quantify the produced cartilage defects. Eight pairs of human cadaver radii with a standardized Mason type II fracture were stabilized either by two 2.0-mm polylactide pins or titanium screws. The produced cartilage defects were quantified using an image analyzing software. Quasi-static loading was performed axially and transversally for 10 cycles each between 10 and 50 N. Afterward, implant loosening was tested by axial loading up to 10,000 cycles, followed by load to failure testing. Polylactide pins showed less construct stiffness under axial (p = 0.017) and transversal (p = 0.012) loading, and one polylactide pins construct failed after two cycles of transversal loading. At axial loading, a high correlation between bone mineral density and construct stiffness was observed among polylactide pins (R = 0.667; p = 0.071), which was not seen among titanium screws (R = 0.262; p = 0.531). No difference in implant loosening was recorded after 10,000 cycles (p = 0.237); however, one polylactide pins construct failed after 30 cycles and failure loads were higher for titanium screws (p=0.017). Polylactide pin produced smaller cartilage defects (p=0.012). In conclusion, simple radial head fractures treated by polylactide pins show less biomechanical stability than treated by titanium screws, particularly in osteoporotic bone which might lead to secondary loss of reduction. Due to smaller cartilage defects and equal properties under continuous loading, polylactide pins might represent a gentle alternative in patients with good bone quality making subsequent implant removal redundant.


Assuntos
Pinos Ortopédicos , Parafusos Ósseos , Traumatismos Craniocerebrais/cirurgia , Fraturas Ósseas/cirurgia , Fenômenos Mecânicos , Titânio/metabolismo , Fenômenos Biomecânicos , Traumatismos Craniocerebrais/metabolismo , Fraturas Ósseas/metabolismo , Teste de Materiais
6.
J Cereb Blood Flow Metab ; 40(2): 446-455, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30667320

RESUMO

Cognitive impairment occurs in stroke and hip fracture patients. In mice, bone fracture (BF) exacerbates stroke-related neuronal damage and sensorimotor dysfunction. We hypothesize that BF exacerbates post-stroke cognitive impairment. Adult mice were randomly assigned into BF, stroke, BF+stroke (BF 6 h before stroke), and control (sham operated) groups. Memory function was evaluated weekly for eight weeks by Y maze test and at eight weeks post-surgeries by novel object recognition (NOR) test. The neuronal damage and inflammation in hippocampus were analyzed three days and eight weeks after the surgeries. In Y maze test, BF+stroke mice started making fewer alternations than controls two weeks after the surgeries. Significant difference between BF+stroke and stroke groups started at five weeks post-injury and continued to the end of the experiment. In NOR test, BF+stroke group spent less time on novel objective than that of other groups. Cx3cr1+ cells and CD68+ cells accumulated in the stratum lacunosum moleculare (SLM) on the ipsilateral side of stroke injury in stroke and BF+stroke mice. BF+stroke mice had a higher ratio of ipsilateral/contralateral Cx3cr1+ cell-density than that of stroke mice. Therefore, BF shortly before stroke exacerbates hippocampal inflammation and causes long-lasting memory dysfunction.


Assuntos
Fraturas Ósseas , Hipocampo , Transtornos da Memória , Memória de Longo Prazo , Acidente Vascular Cerebral , Animais , Fraturas Ósseas/complicações , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Fraturas Ósseas/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
7.
Front Immunol ; 10: 2662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781128

RESUMO

Despite high biocompatibility of titanium and its alloys, this metal causes various side effects in the human body. It is believed that titanium biomaterials may induce an innate/adaptive immune response. However, still little is known about changes caused by titanium mandible implants, particularly with regard to bone healing. The latest studies showed disturbances in the antioxidant barrier, increased oxidative/nitrosative stress, as well as mitochondrial abnormalities in the periosteum covering titanium mandible fixations; nevertheless, the impact of titanium implants on free radical production, inflammation, and mandible apoptosis are still unknown. Because severe inflammation and apoptosis are among the main factors responsible for disturbances in osteointegration as well as implant rejection, this study is the first to evaluate pro-oxidant enzymes, cytokines as well as pro- and anti-apoptotic proteins in the periosteum of patients with a broken jaw, treated with titanium miniplates and miniscrews. The study group consisted of 29 patients with double-sided fracture of the mandible body requiring surgical treatment. We found significantly higher activity of NADPH oxidase and xanthine oxidase as well as enhanced rate of free radical production in the periosteum of patients in the study group compared to the control group. The markers of inflammation [interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), transforming growth factor ß (TGF-ß) and ß-glucuronidase (GLU)] as well as apoptosis [Bax, Bax/Bcl-2 ratio, caspase-3 (CAS-3) and nitric oxide (NO)] were significantly elevated in periosteum covering titanium fixations compared to the control group. In the study group, we also demonstrated an increased content of titanium on the periosteum surface, which positively correlated with CAS-3 activity. The study led us to the conclusion that titanium mandible implants increase the production of pro-inflammatory cytokines, and enhance free radical generation in the periosteum covering titanium miniplates and miniscrews. Additionally, exposure to Ti6Al4V titanium alloy induces apoptosis in the mandible periosteum. However, no clinical signs of the said phenomena have been observed.


Assuntos
Fraturas Ósseas/terapia , Traumatismos Mandibulares/terapia , Prótese Mandibular/efeitos adversos , Titânio/efeitos adversos , Adulto , Apoptose , Caspase 3/metabolismo , Citocinas/metabolismo , Feminino , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Radicais Livres/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Traumatismos Mandibulares/metabolismo , Traumatismos Mandibulares/patologia , NADPH Oxidases/metabolismo , Periósteo/química , Periósteo/metabolismo , Periósteo/patologia , Titânio/análise , Xantina Oxidase/metabolismo , Adulto Jovem
8.
Fertil Steril ; 112(5): 782-790, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31731932

RESUMO

Fractures and their consequences are the clinically important manifestation of osteoporosis; preventing fractures is the primary goal of management. Effective management is achievable given present knowledge and tools but is seldom prescribed. This review will cover the individual and social burden of fracture, essential information about fracture risk and its estimation, an approach to patient care emphasizing specific information to elicit and therapeutic strategies to pursue, and existing gaps in knowledge and important questions for future research.


Assuntos
Densidade Óssea/fisiologia , Gerenciamento Clínico , Fraturas Ósseas/metabolismo , Fraturas Ósseas/terapia , Perimenopausa/metabolismo , Pós-Menopausa/metabolismo , Adulto , Feminino , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Fatores de Risco
9.
Fertil Steril ; 112(5): 791-798, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31731933

RESUMO

Osteoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men. Men are screened less and more frequently undertreated than female patients. It is the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men.


Assuntos
Densidade Óssea/fisiologia , Fraturas Ósseas/terapia , Necessidades e Demandas de Serviços de Saúde , Osteoporose/terapia , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/metabolismo , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Masculino , Osteoporose/diagnóstico , Osteoporose/metabolismo , Fatores de Risco
10.
Chin J Traumatol ; 22(6): 311-315, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31685356

RESUMO

PURPOSE: To study the effect of early restrictive fluid resuscitation (EFR) on inflammatory and immune factors in patients with severe pelvic fracture (SPF). METHODS: A total of 174 SPF patients in the Department of Orthopaedics, the First Affiliated Hospital of Chengdu Medical College from July 2015 to June 2018 were involved in this study and divided into EFR group (n = 87) and control group (n = 87) using the random number table method. Conventional fluid resuscitation (CFR) was performed in control group, and EFR was performed in EFR group. The incidences of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) during rescue, successful rescue rate, blood transfusion volume, fluid input, and resuscitation time were compared between the two groups. The parameters including prothrombin time (PT), hematocrit (HCT), platelet (PLT) and blood lactate (BL) at the 4th hour after fluid resuscitation were recorded. The levels of inflammatory factors (TNF-α, IL-6, CRP) and immune factors (CD3+, CD4+, CD8+, CD4+/CD8+) were compared between the two groups before treatment and 7 days after treatment. The revised acute physiologic and chronic health evaluation system and the sequential organ failure assessment scores were adopted for evaluation before treatment and 7 days after treatment. RESULTS: The incidences of ARDS and MODS during rescue in EFR group were significantly lower than those in control group (p=0.015 and 0.010 respectively), and the successful rescue rate in EFR group was significantly higher than that in control group (p = 0.011). The blood transfusion volume, fluid input, resuscitation time in EFR group were significantly lower than those in control group (p = 0.016, 0.002 and 0.001 respectively). At the 4th hour after fluid resuscitation, PT and BL in EFR group were significantly lower than those in control group (p = 0.021 and 0.003 respectively), while HCT and PLT in EFR group were significantly higher than those in control group (p = 0.016 and 0.021 respectively). On day 7 after treatment, TNF-α, IL-6, CRP and CD8+ in EFR group were significantly lower than those in control group (p = 0.003, 0.004, 0.007 and 0.003 respectively), while CD3+, CD4+ and CD4+/CD8+ in EFR group were significantly higher than those in control group (p = 0.004, 0.000, 0.007 respectively). On day 7 after treatment, the revised acute physiologic and chronic health evaluation (APACHE) system and the sequential organ failure assessment (SOFA) scores in EFR group were significantly lower than those in control group. CONCLUSION: EFR can effectively eliminate inflammatory factors, improve immune function, maintain the stability of blood components, reduce the incidences of ARDS and MODS, and elevate the successful rescue rate in patients with SPF.


Assuntos
Hidratação/métodos , Fraturas Ósseas/imunologia , Fraturas Ósseas/metabolismo , Fatores Imunológicos/metabolismo , Ossos Pélvicos/lesões , Ressuscitação/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Inflamação , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/prevenção & controle , Fatores de Tempo , Adulto Jovem
11.
Sci Rep ; 9(1): 16994, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740777

RESUMO

Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p < 0.05) 4 weeks after the onset of DM1 when compared with control. Diffuse damage density was highest at 12 weeks after the onset of DM1. The arrangement of the collagen fibrils became progressively more irregular from 4 to 24 weeks of DM. This is the first study to analyze microdamage in vivo at different time points of DM1. DM1is associated with microcracks from the early stage, however bone microstructure shows toughening mechanisms that arrest their growth but disease progression further deteriorates bone quality resulting in longer microcracks which may increase fracture risk.


Assuntos
Densidade Óssea , Osso e Ossos/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Estresse Mecânico , Animais , Osso e Ossos/metabolismo , Osso e Ossos/ultraestrutura , Força Compressiva , Modelos Animais de Doenças , Corantes Fluorescentes/metabolismo , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Masculino , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Ratos Wistar , Fatores de Tempo
12.
J Clin Invest ; 129(12): 5137-5150, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31638597

RESUMO

Bone is richly innervated by nerve growth factor-responsive (NGF-responsive) tropomyosin receptor kinase A-expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little is known regarding the role of sensory innervation in bone repair. Here, we characterized the reinnervation of tissue following experimental ulnar stress fracture and assessed the impact of loss of TrkA signaling in this process. Sequential histological data obtained in reporter mice subjected to fracture demonstrated a marked upregulation of NGF expression in periosteal stromal progenitors and fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum in NGF-enriched cellular domains were evident at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed ossification of the fracture callus. We observed similar deficiencies in nerve regrowth and fracture healing in a mouse model of peripheral neuropathy induced by paclitaxel treatment. Together, our studies demonstrate an essential role of TrkA signaling for stress fracture repair and implicate skeletal sensory nerves as an important upstream mediator of this repair process.


Assuntos
Consolidação da Fratura , Fraturas Ósseas/metabolismo , Receptor trkA/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Modelos Animais de Doenças , Fraturas de Estresse , Gânglios Espinais/metabolismo , Genes Reporter , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/metabolismo , Osteogênese , Periósteo/metabolismo , Transdução de Sinais , Células-Tronco , Transgenes , Microtomografia por Raio-X
13.
In Vivo ; 33(6): 1813-1818, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662507

RESUMO

BACKGROUND/AIM: In Korea, small breed dogs including Maltese, Pomeranians, and Yorkshire Terriers are most common. These small dogs are at increased risk for the development of delayed union or nonunion fractures, particularly when the fracture occurs at a site with insufficient surrounded soft tissue such as the ulna and radius. To treat failed bone fracture healing, stable fixation of the fracture and implantation of bone grafts are needed. Among the various types of bone grafts, autograft is considered to be the gold standard. However, the amount of autograft available for harvesting in small dogs is limited. In this study, we report on a novel canine cancellous allograft (C350C) that was prepared using chemicals and low heat treatment (350°C). PATIENTS AND METHODS: We applied C350C in two cases with failed bone fracture healing. Due to the poor osteoinductive capabilities of C350C, we also used recombinant human bone morphogenetic protein-2 (rhBMP-2) and Matrigel as osteoinductive and delivery agents, respectively. RESULTS: In both cases, the fractures healed successfully. CONCLUSION: C350C can be used as a bone graft material that could replace autografts in cases with failed bone fracture healing.


Assuntos
Consolidação da Fratura/fisiologia , Fraturas Ósseas/cirurgia , Aloenxertos/metabolismo , Aloenxertos/cirurgia , Animais , Proteína Morfogenética Óssea 2/metabolismo , Transplante Ósseo/métodos , Cães , Fraturas Ósseas/metabolismo , Masculino , Proteínas Recombinantes/metabolismo , República da Coreia , Fator de Crescimento Transformador beta/metabolismo , Transplante Autólogo/métodos , Transplante Homólogo/métodos
14.
Tissue Eng Part C Methods ; 25(12): 732-741, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31663423

RESUMO

Most histological evaluations of critical-sized bone defects are limited to the analysis of a few regions of interest at a time. Manual and semiautomated histomorphometric approaches often have intra- and interobserver subjectivity, as well as variability in image analysis methods. Moreover, the production of large image data sets makes histological assessment and histomorphometric analysis labor intensive and time consuming. Herein, we tested and compared two image segmentation methods: thresholding (automated) and region-based (manual) modes, for quantifying complete image sets across entire critical-sized bone defects, using the widely used Osteomeasure system and the freely downloadable Aperio Image Scope software. A comparison of bone histomorphometric data showed strong agreement between the automated segmentation mode of the Osteomeasure software with the manual segmentation mode of Aperio Image Scope analysis (bone formation R2 = 0.9615 and fibrous tissue formation R2 = 0.8734). These results indicate that Aperio is capable of handling large histological images, with excellent speed performance in producing highly consistent histomorphometric evaluations compared with the Osteomeasure image analysis system. The statistical evaluation of these two major bone parameters demonstrated that Aperio Image Scope is as capable as Osteomeasure. This study developed a protocol to improve the quality of results and reduce analysis time, while also promoting the standardization of image analysis protocols for the histomorphometric analysis of critical-sized bone defect samples. Impact Statement Despite bone tissue engineering innovations increasing over the last decade, histomorphometric analysis of large bone defects used to study such approaches continues to pose a challenge for pathological assessment. This is due to the resulting large image data set, and the lack of a gold standard image analysis protocol to quantify histological outcomes. Herein, we present a standardized protocol for the image analysis of critical-sized bone defect samples stained with Goldner's Trichrome using the Osteomeasure and Aperio Image Scope image analysis systems. The results were critically examined to determine their reproducibility and accuracy for analyzing large bone defects.


Assuntos
Fraturas Ósseas , Processamento de Imagem Assistida por Computador , Osteogênese , Software , Animais , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Ovinos
15.
Bone ; 128: 115038, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31446116

RESUMO

This paper is concerned with the effect of different strain rate on the Work of Fracture (Wf) of various vertebrate mineralised tissues, controlling for the effect of mineral content and Young's modulus of elasticity. Using specimens of uniform shape and size values for the Work of Fracture of specimens tested at various deformation rates, and also the energy absorbed by notched specimens in impact, are reported. The results indicated that, of those tested, for most bone specimens the Work of Fracture measurements were constant like in the case for a 'material property'. Variations due to loading conditions (deformation rate) were small, with the exemption of antler, which is relatively poorly mineralised and in which the Work of Fracture values increased by a factor of 4 across the range from quasistatic loading to impact. The Tattersall and Tappin (1966) test has shown itself to offer some great advantages: if the quest is for a fracture toughness test for an unknown tissue it offers reliability, it is perhaps more forgiving to handling errors, it also suffers less of the influence of strain rate effects and uses relatively simple instrumentation. It is also able to demonstrate the remarkable toughness of antler bone which other more commonly used fracture toughness methods cannot do.


Assuntos
Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Animais , Chifres de Veado , Densidade Óssea/fisiologia , Osso e Ossos , Bovinos , Módulo de Elasticidade/fisiologia , Microscopia Eletroquímica de Varredura , Estresse Mecânico
16.
Osteoporos Int ; 30(12): 2381-2389, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446441

RESUMO

To assess the time from fracture until bone turnover markers (BTM), which are biochemical markers reflecting in vivo bone formation and resorptive activity, have returned to a stable level since BTM have been shown to be at least as good as bone mineral density in monitoring the effect of anti-resorptive treatment in osteoporosis. This study searched for articles in PUBMED, CINAHL, Medline, EM-BASE, and Cochrane, and identified 3486 unique articles. These articles were screened based on predefined inclusion and exclusion criteria. Seven articles addressing time to normalization of either CTX, PINP, osteocalcin, or bone-specific alkaline phosphatase after a recent fracture were identified and these were analyzed qualitatively. CTX appeared to return to baseline within 6 months. PINP appeared to return to baseline within 6 months and interestingly dip below baseline after a year. Osteocalcin was elevated throughout the first year after a fracture, with most changes in the first 6 months. Bone-specific alkaline phosphatase (BAP) was increased for up to a year, however with a discrepancy between used assays. Seven studies were identified, showing CTX and PINP to return to baseline within 6 months. OC was elevated for 12 months. BAP was increased for up to a year. However, none of these studies had fasting patients and a long follow-up period with regular measurements. The studies could indicate that the BTM CTX and PINP have returned to baseline within 6 months; however, further studies are needed assessing pre-analytical factors while having a long follow-up. Bone turnover markers appear as good as or better than bone mineral density in monitoring the effect of anti-resorptive medication in osteoporosis. This study tries to identify the time from fracture until BTM are back at baseline. Most studies did not however take pre-analytical variation into consideration. Further research is therefore needed.


Assuntos
Biomarcadores/metabolismo , Remodelação Óssea/fisiologia , Fraturas Ósseas/metabolismo , Fosfatase Alcalina/metabolismo , Colágeno Tipo I/metabolismo , Fraturas Ósseas/fisiopatologia , Humanos , Osteocalcina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Pró-Colágeno/metabolismo
17.
Sci Rep ; 9(1): 12199, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434912

RESUMO

Polytraumatic injuries, specifically long bone fracture and traumatic brain injury (TBI), frequently occur together. Clinical observation has long held that TBI can accelerate fracture healing, yet the complexity and heterogeneity of these injuries has produced conflicting data with limited information on underlying mechanisms. We developed a murine polytrauma model with TBI and fracture to evaluate healing in a controlled system. Fractures were created both contralateral and ipsilateral to the TBI to test whether differential responses of humoral and/or neuronal systems drove altered healing patterns. Our results show increased bone formation after TBI when injuries occur contralateral to each other, rather than ipsilateral, suggesting a role of the nervous system based on the crossed neuroanatomy of motor and sensory systems. Analysis of the humoral system shows that blood cell counts and inflammatory markers are differentially modulated by polytrauma. A data-driven multivariate analysis integrating all outcome measures showed a distinct pathological state of polytrauma and co-variations between fracture, TBI and systemic markers. Taken together, our results suggest that a contralateral bone fracture and TBI alter the local neuroinflammatory state to accelerate early fracture healing. We believe applying a similar data-driven approach to clinical polytrauma may help to better understand the complicated pathophysiological mechanisms of healing.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Fraturas Ósseas/metabolismo , Traumatismo Múltiplo/metabolismo , Animais , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Fraturas Ósseas/patologia , Masculino , Camundongos , Traumatismo Múltiplo/patologia
18.
Eur Rev Med Pharmacol Sci ; 23(13): 5558-5566, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31298307

RESUMO

OBJECTIVE: To measure the expression level of long non-coding ribonucleic acids (lncRNAs) differentiation antagonizing non-protein coding RNA (DANCR) in serum of patients with fracture and investigate its influences on the proliferation and differentiation of osteoblasts. PATIENTS AND METHODS: Serum samples were collected from 44 fracture patients treated in our hospital and 24 healthy people receiving physical examination in our hospital. Then, reverse transcription-polymerase chain reaction (RT-PCR) technique was used to detect the expression of lncRNA DANCR in the serum of patients with fracture and healthy subjects. MC3T3-E1 mouse osteoblast cell line with stably-knocked out DANCR was further established using small interfering RNAs (siRNAs), and the effect of DANCR knockout on the proliferation of osteoblasts was determined using cell counting kit-8 (CCK-8). At the same time, 5-Ethynyl-2'-deoxyuridine (EdU) staining assay was performed to detect the percentage of EdU-positive cells in osteoblasts in control group and DANCR knockout group. In addition, the mRNA levels of differentiation-related genes including Runt-related transcription factor 2 (Runx2), Collagen1α1, osteocalcin (OC) and osterix (OSX) were detected via RT-PCR, and the protein level of Runx2 was measured through Western blotting. Moreover, osteoblasts were cultured with osteogenic medium for 14 d, and then alizarin red staining and alkaline phosphatase (ALP) staining assays were carried out to examine the differentiation of these osteoblasts. Lastly, Western blotting technique was employed to analyze the expression of the Wnt/ß-catenin signaling pathway. RESULTS: The expression of lncRNA DANCR was significantly increased in the serum of fracture patients (p<0.05). The results of in-vitro cell experiments showed that the intervention of DANCR with siRNA was able to clearly promote the proliferation and differentiation of MC3T3-E1 osteoblast cell line. According to the results of Western blotting, DANCR promoted the apoptosis and proliferation, which was mediated by the activated Wnt/ß-catenin signaling pathway in osteoblasts. CONCLUSIONS: LncRNA DANCR inhibition can facilitate the proliferation and differentiation of osteoblasts by activating the Wnt/ß-catenin signaling pathway in osteoblasts. Therefore, DANCR is expected to be a new target promoting fracture healing.


Assuntos
Diferenciação Celular , Proliferação de Células , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt , Adulto , Animais , Estudos de Casos e Controles , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Humanos , Camundongos , Pessoa de Meia-Idade , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogênese , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/sangue , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo
19.
J Bone Miner Res ; 34(11): 2052-2060, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31310354

RESUMO

Although a relationship between vascular disease and osteoporosis has been recognized, its clinical importance for fracture risk evaluation remains uncertain. Abdominal aortic calcification (AAC), a recognized measure of vascular disease detected on single-energy images performed for vertebral fracture assessment, may also identify increased osteoporosis risk. In a prospective 10-year study of 1024 older predominantly white women (mean age 75.0 ± 2.6 years) from the Perth Longitudinal Study of Aging cohort, we evaluated the association between AAC, skeletal structure, and fractures. AAC and spine fracture were assessed at the time of hip densitometry and heel quantitative ultrasound. AAC was scored 0 to 24 (AAC24) and categorized into low AAC (score 0 and 1, n = 459), moderate AAC (score 2 to 5, n = 373), and severe AAC (score >6, n = 192). Prevalent vertebral fractures were calculated using the Genant semiquantitative method. AAC24 scores were inversely related to hip BMD ( r s = -0.077, p = 0.013), heel broadband ultrasound attenuation ( r s = -0.074, p = 0.020), and the Stiffness Index ( r s = -0.073, p = 0.022). In cross-sectional analyses, women with moderate to severe AAC were more likely to have prevalent fracture and lumbar spine imaging-detected lumbar spine fractures, but not thoracic spine fractures (Mantel-Haenszel test of trend p < 0.05). For 10-year incident clinical fractures and fracture-related hospitalizations, women with moderate to severe AAC (AAC24 score >1) had increased fracture risk (HR 1.48; 95% CI, 1.15 to 1.91; p = 0.002; HR 1.46; 95% CI, 1.07 to 1.99; p = 0.019, respectively) compared with women with low AAC. This relationship remained significant after adjusting for age and hip BMD for clinical fractures (HR 1.40; 95% CI, 1.08 to 1.81; p = 0.010), but was attenuated for fracture-related hospitalizations (HR 1.33; 95% CI, 0.98 to 1.83; p = 0.073). In conclusion, older women with more marked AAC are at higher risk of fracture, not completely captured by bone structural predictors. These findings further support the concept that vascular calcification and bone pathology may share similar mechanisms of causation that remain to be fully elucidated © 2019 American Society for Bone and Mineral Research.


Assuntos
Aorta Abdominal/metabolismo , Doenças da Aorta , Densidade Óssea , Fraturas Ósseas , Hospitalização , Calcificação Vascular , Idoso , Idoso de 80 Anos ou mais , Doenças da Aorta/complicações , Doenças da Aorta/epidemiologia , Doenças da Aorta/metabolismo , Doenças da Aorta/terapia , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/metabolismo , Fraturas Ósseas/terapia , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Calcificação Vascular/complicações , Calcificação Vascular/epidemiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/terapia
20.
FASEB J ; 33(10): 11163-11179, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31307226

RESUMO

Osteoporosis is a common skeletal disease, affecting millions of individuals worldwide. Currently used osteoporosis treatments substantially reduce vertebral fracture risk, whereas nonvertebral fracture risk, mainly caused by reduced cortical bone mass, has only moderately been improved by the osteoporosis drugs used, defining an unmet medical need. Because several wingless-type MMTV integration site family members (WNTs) and modulators of WNT activity are major regulators of bone mass, we hypothesized that NOTUM, a secreted WNT lipase, might modulate bone mass via an inhibition of WNT activity. To characterize the possible role of endogenous NOTUM as a physiologic modulator of bone mass, we developed global, cell-specific, and inducible Notum-inactivated mouse models. Notum expression was high in the cortical bone in mice, and conditional Notum inactivation revealed that osteoblast lineage cells are the principal source of NOTUM in the cortical bone. Osteoblast lineage-specific Notum inactivation increased cortical bone thickness via an increased periosteal circumference. Inducible Notum inactivation in adult mice increased cortical bone thickness as a result of increased periosteal bone formation, and silencing of Notum expression in cultured osteoblasts enhanced osteoblast differentiation. Large-scale human genetic analyses identified genetic variants mapping to the NOTUM locus that are strongly associated with bone mineral density (BMD) as estimated with quantitative ultrasound in the heel. Thus, osteoblast-derived NOTUM is an essential local physiologic regulator of cortical bone mass via effects on periosteal bone formation in adult mice, and genetic variants in the NOTUM locus are associated with BMD variation in adult humans. Therapies targeting osteoblast-derived NOTUM may prevent nonvertebral fractures.-Movérare-Skrtic, S., Nilsson, K. H., Henning, P., Funck-Brentano, T., Nethander, M., Rivadeneira, F., Coletto Nunes, G., Koskela, A., Tuukkanen, J., Tuckermann, J., Perret, C., Souza, P. P. C., Lerner, U. H., Ohlsson, C. Osteoblast-derived NOTUM reduces cortical bone mass in mice and the NOTUM locus is associated with bone mineral density in humans.


Assuntos
Densidade Óssea/genética , Osso Cortical/metabolismo , Osso Cortical/fisiologia , Esterases/metabolismo , Osteoblastos/metabolismo , Animais , Densidade Óssea/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Esterases/genética , Feminino , Fraturas Ósseas/metabolismo , Fraturas Ósseas/fisiopatologia , Variação Genética/genética , Humanos , Masculino , Camundongos , Osteogênese/genética , Osteogênese/fisiologia , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Proteínas Wnt/metabolismo
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