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Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, in Fig. 2A on p. 8311, portraying the results of immunostaining experiments for osterix, the 'GIOP' and 'GIOP+TMP (20)' data panels contained overlapping data, such that these images were derived from apparently the same original source, where they were intended to show the results from differently performed experiments. Moreover, in Fig. 3A on p. 8312 showing the results from ALP staining and Alizarin Red S staining experiments, two pairs of apparently overlapping data panels were identified in the Dex 106 M / TMP 50 µM, 100 µM and 200 µM data panels. After having reexamined their original data, the authors have realized that the data featured in Figs. 2A and 3A were assembled incorrectly in these figures. Revised versions of Fig. 2 and 3, now containing replacement data for the experiments shown in Figs. 2A and 3A, are shown on the next page. Note that these errors did not adversely affect either the results or the overall conclusions reported in this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 16: 83078314, 2017; DOI: 10.3892/mmr.2017.7610].
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OBJECTIVE: To compare the clinical efficacy of the minimally invasive technique and the open method in the treatment of irreducible unilateral subaxial cervical facet joint dislocation (SCFD). METHODS: From March 2015 to September 2018, 62 patients with unilateral SCFD were studied. The cases were divided into 2 groups based on different surgery strategies. Thirty-one patients were enrolled in the minimally invasive surgery (MIS) group, and 31 patients were enrolled in the open surgery group. The duration of prone position operation, blood loss, and total hospitalization costs were recorded. The clinical effects were evaluated using visual analogue scale scores, the Oswestry Disability Index, and Japanese Orthopedic Association scores at each follow-up. In addition, the segmental Cobb angle and intervertebral height were recorded and compared. RESULTS: The amount of intraoperative blood loss, prone position operation duration, and total hospital costs in the MIS group were significantly lower than in the open surgery group. The visual analogue scale, Oswestry Disability Index, and Japanese Orthopedic Association scores of the 2 groups significantly improved after the operation. A satisfactory fusion rate was obtained in both groups, and the segmental Cobb angle and intervertebral height scores in both groups improved significantly. CONCLUSIONS: Minimally invasive reduction had equal clinical efficacy to posterior open surgery. However, MIS was less invasive and had lower costs. Therefore, it is a potential option in the treatment of SCFD.
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Luxaciones Articulares , Fusión Vertebral , Articulación Cigapofisaria , Humanos , Fusión Vertebral/métodos , Resultado del Tratamiento , Articulación Cigapofisaria/diagnóstico por imagen , Articulación Cigapofisaria/cirugía , Luxaciones Articulares/diagnóstico por imagen , Luxaciones Articulares/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos , Vértebras Lumbares/cirugía , Estudios RetrospectivosRESUMEN
Diagnosis of rare skeletal diseases is based primarily on clinical phenotype and radiographic analysis. Genetic etiology of these heterogeneous diseases remains largely unknown. Here, we report the identification of two genomic mutations using exome sequencing from patients with multiple epiphyseal dysplasia (MED) of an unusual family in autosomal dominant and X-linked inheritance. A dominant mutation (c.2224G > A; p.Gly687Ser) in the known causal COL2A1 gene was identified in three patients with MED, deformed femoral heads and vertebral dysplasia. Furthermore, a hemizygous mutation (c.2830G > A; p.Ala944Thr) in the USP9X gene was identified in the fourth patient with short stature, MED, deformed femoral head, thoracic and lumbar platyspondyly, right ankle condyle dysplasia, and subchondral sclerosis. This is the first identification of an X-linked candidate causative gene in a patient with MED, suggesting a new clinical entity. Our findings shed a new light on the role of USP9X in MED-associated disorders.
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Osteocondrodisplasias , Colágeno Tipo II , Exoma , Humanos , Mutación , Linaje , Ubiquitina Tiolesterasa , Secuenciación del ExomaRESUMEN
OBJECTIVE: An optimized Enhanced Recovery After Surgery (ERAS) program is lacking for adolescent idiopathic scoliosis (AIS). The aim of the present study was to evaluate the impact and feasibility of an optimized ERAS pathway in patients with surgically treated AIS. METHODS: In total, 79 patients with AIS who underwent corrective surgery without 3-column osteotomy were recruited from Xijing Hospital of the Fourth Military Medical University between 2012 and 2018. Forty-four patients were treated according to a traditional protocol and 35 were managed using an optimized ERAS pathway, which was designed and implemented by a multidisciplinary team. The following data were collected and retrospectively analyzed, demographic characteristics, Cobb angle, curve type (Lenke), surgical duration, fusion level, correction rate, estimated blood loss, postoperative hemoglobin level, postoperative pain score, pain relief time, hemovac drainage, drainage removal time, first ambulation time, length of hospital stay, and postoperative complications. RESULTS: There was no significant difference between the traditional and ERAS groups with respect to demographic characteristics, Cobb angle, curve type (Lenke), fusion level, and correction rate. However, the ERAS group had a shorter surgical duration, less blood loss and hemovac drainage, a higher postoperative hemoglobin level, and earlier pain relief, ambulation, and discharge. The rates of postoperative nausea and vomiting were lower in the ERAS group than in the traditional group. CONCLUSIONS: The ERAS pathway is capable of improving the perioperative status of patients with AIS by offering stronger analgesia, faster ambulation, and earlier discharge.
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Recuperación Mejorada Después de la Cirugía , Escoliosis/cirugía , Adolescente , Estudios de Cohortes , Femenino , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Fusión Vertebral/efectos adversos , Fusión Vertebral/métodosRESUMEN
AIMS: The intervertebral disc is the largest avascular organ of the body. Vascularization of the disc has been typically regarded as a pathological feature of intervertebral disc degeneration (IDD). However, the underlying mechanism of vascularization in IDD is still unclear. The current study aimed to investigate the role of AF cell derived exosome (AF-exo) in the interaction with human umbilical vein endothelial cells (HUVECs) and its potential role in the regulation of vascularization in IDD. MAIN METHODS: Human AF tissues were obtained from patients with IDD and idiopathic scoliosis. The AF-exo were isolated and identified by transmission electron microscopy (TEM), nanoparticle trafficking analysis (NTA) and Western blotting. Then, the AF-exo were used for HUVECs cultures. The migration of HUVECs was observed in 2D and 3D cultures. The inflammatory phenotype of HUVECs was examined by Real-time PCR and enzyme-linked immunosorbent assay (ELISA). Additionally, apoptosis of HUVECs were analyzed by flow cytometry. KEY FINDINGS: Here, we for the first time found that AF cells could secrete AF-exo and that the AF-exo could be phagocytosed by HUVECs. Additionally, we found that degenerated AF-exo exerted pro-vascularization effect on HUVECs by promoting cell migration (in 2D and 3D cultures) and inflammatory factor expression including IL-6, TNF-α, MMP-3, MMP-13 and VEGF, whereas the application of non-degenerated AF-exo demonstrated inverse effects. SIGNIFICANCE: These results showed that AF-exo is an essential regulator mediating intercellular communication between AF cells and HUVECs, suggesting its important role in vascularization in the intervertebral disc.
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Anillo Fibroso/metabolismo , Movimiento Celular/fisiología , Endotelio/citología , Exosomas/metabolismo , Inflamación/fisiopatología , Degeneración del Disco Intervertebral/patología , Disco Intervertebral/irrigación sanguínea , Adolescente , Adulto , Anciano , Anillo Fibroso/fisiología , Apoptosis , Western Blotting , Endotelio/metabolismo , Endotelio/fisiología , Citometría de Flujo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/fisiopatología , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Escoliosis/metabolismo , Escoliosis/fisiopatología , Adulto JovenRESUMEN
Angiogenesis is a pathological signature of intervertebral disc degeneration (IDD). Accumulating evidence has shown that notochordal cells (NCs) play an essential role in maintaining intervertebral disc development and homeostasis with inhibitive effect on blood vessel in-growth. However, the anti-angiogenesis mechanism of NCs is still unclear. In the current study, we, for the first time, isolated NC-derived exosomes (NC-exos) and showed their increased concentration following compressive load cultures. We further found that NC-exos from 0.5 MPa compressive load cultures (0.5 MPa/NC-exos) inhibit angiogenesis via transferring high expressed microRNA (miR)-140-5p to endothelial cells and regulating the downstream Wnt/ß-catenin pathway. Clinical evidence showed that exosomal miR-140-5p expression of the nucleus pulposus is negatively correlated with angiogenesis in IDD. Finally, 0.5 MPa/NC-exos were demonstrated to have a therapeutical impact on the degenerated disc with an anti-angiogenesis effect in an IDD model. Consequently, our present findings provide insights into the anti-angiogenesis mechanism of NC-exos, indicating their therapeutic potential for IDD.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The intervertebral disc (IVD) is the largest avascular organ of the body. It is composed of three parts: the nucleus pulposus (NP), the annulus fibrosus (AF) and the cartilaginous endplate (CEP). The central NP is surrounded by the AF and sandwiched by the two CEPs ever since its formation. This unique structure isolates the NP from the immune system of the host. Additionally, molecular factors expressed in IVD have been shown inhibitive effect on immune cells and cytokines infiltration. Therefore, the IVD has been identified as an immune privilege organ. The steady state of immune privilege is fundamental to the homeostasis of the IVD. The AF and the CEP, along with the immunosuppressive molecular factors are defined as the blood-NP barrier (BNB), which establishes a strong barrier to isolate the NP from the host immune system. When the BNB is damaged, the auto-immune response of the NP occurs with various downstream cascade reactions. This effect plays an important role in the whole process of IVD degeneration and related complications, such as herniation, sciatica and spontaneous herniated NP regression. Taken together, an enhanced understanding of the immune privilege of the IVD could provide new targets for the treatment of symptomatic IVD disease. However, the underlying mechanism above is still not fully clarified. Accordingly, the current study will extensively review and discuss studies regarding the immune privilege of the IVD.
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Privilegio Inmunológico , Degeneración del Disco Intervertebral/terapia , Disco Intervertebral/inmunología , HumanosRESUMEN
Osteoporosis and intervertebral disc degeneration (IDD) are both age-related diseases of the musculoskeletal system. With the average life expectancy longer than ever, the morbidity caused by these two diseases is increasing. Nowadays, treatment strategies for osteoporosis are mainly aimed at increasing the mineral density of the bone. Some of these therapies, including vitamin D, calcium, bisphosphonates, Wnt signal activators and parathyroid hormone regulators, have been suggested to be capable of causing calcification of the cartilage endplate in the intervertebral disc. This alteration could block nutrient and oxygen transportation to the center part of the disc, thus lead to intervertebral disc degeneration. Consequently, we hypothesize that osteoporosis therapies might be a potential risk for IDD. This assumption indicates that we should take the alterations of the cartilage endplate into consideration in further osteoporosis treatment to avoid IDD in the patient.
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Conservadores de la Densidad Ósea/efectos adversos , Cartílago/patología , Degeneración del Disco Intervertebral/patología , Osteoporosis/tratamiento farmacológico , Anillo Fibroso/fisiología , Densidad Ósea , Calcinosis , Calcio/metabolismo , Difosfonatos/efectos adversos , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/prevención & control , Núcleo Pulposo/fisiología , Osteoporosis/complicaciones , Hormona Paratiroidea/metabolismo , Riesgo , Vitamina D/metabolismo , Proteínas Wnt/metabolismoRESUMEN
BACKGROUND: Alendronate has been used to prevent or treat glucocorticoid-induced osteoporosis (GIO), data regarding its efficacy are inconsistent. We conducted the current systematic review and meta-analysis to evaluate both efficacy and safety of alendronate in the treatment of GIO. METHODS: PubMed, Embase, the Cochrane Controlled Trials Registry, and the China Academic Journal Network Publishing Databases were searched up through March 1, 2018. Randomized controlled trials (RCTs) involving patients which received alendronate treatment were included. Outcome measures were bone mineral density (BMD) changes, bone fractures, and adverse reactions. Data from the individual studies were pooled using random or fixed effect models based on heterogeneity. Effect size was reported as standardized mean differences (SMD) for continuous outcomes and pooled odds ratios (OR) for dichotomous outcomes, with 95% confidence interval (CI). RESULTS: Overall, 10 studies involving 1002 patients were included in the present investigation. Alendronate treatment significantly increased BMD of the lumbar spine and femoral neck during 6 to 24 months. These beneficial effects were apparent at 12 months after treatment for the lumbar spine but not the femoral neck BMD. Alendronate treatment did not significantly change fracture risk nor induce significant differences in adverse gastrointestinal effects. CONCLUSION: Alendronate significantly increases BMD of the lumbar spine and femoral neck in patients with GIO, but does not appear to reduce the risk of fractures. As relatively insufficient data regarding the GIO fracture incidence has been reported, more RCTs need to be carried out to determine the efficacy of alendronate in the prevention of GIO fracture.
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Alendronato/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Glucocorticoides/efectos adversos , Osteoporosis/inducido químicamente , Alendronato/efectos adversos , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/efectos adversos , Femenino , Humanos , Masculino , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Longitudinally oriented microstructures are essential for a nerve scaffold to promote the significant regeneration of injured peripheral axons across nerve gaps. In the current study, we present a novel nerve-guiding collagen-chitosan (CCH) scaffold that facilitated the repair of 30 mm-long sciatic nerve defects in beagles. The CCH scaffolds were observed with a scanning electron microscope. Eighteen beagles were equally divided into CCH group, autograft group and non-graft group. The posture and gait of each dog was recorded at 12 and 24 weeks after surgery. Electrophysiological tests, Fluoro-Gold retrograde tracing test, Histological assessment of gastrocnemius and immunofluorescent staining of nerve regeneration were performed. Our investigation of regenerated sciatic nerves indicated that a CCH scaffold strongly supported directed axon regeneration in a manner similar to that achieved by autologous nerve transplantation. In vivo animal experiments showed that the CCH scaffold achieved nerve regeneration and functional recovery equivalent to that achieved by an autograft but without requiring the exogenous delivery of regenerative agents or cell transplantation. We conclude that CCH nerve guides show great promise as a method for repairing peripheral nerve defects.
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Regeneración Nerviosa/fisiología , Nervio Ciático/fisiopatología , Neuropatía Ciática/patología , Animales , Materiales Biocompatibles/química , Quitosano/química , Perros , Masculino , Modelos Animales , Prótesis e Implantes , Recuperación de la Función , Neuropatía Ciática/cirugía , Ingeniería de TejidosRESUMEN
Longterm glucocorticoid therapy results in various side effects, including a high incidence of glucocorticoidinduced osteoporosis (GIOP), which is the most common form of secondary osteoporosis. Excess glucocorticoids reduce the viability of bone marrowderived mesenchymal stem cells (BMSCs) and prolong osteoclast survival. These two types of cell are essential in the balance between bone formation and resorption. Tetramethylpyrazine (TMP), the pharmacologically active component extracted from Chuanxiong, has been reported to protect BMSCs from glucocorticoidinduced apoptosis. In the present study, the protective effects of TMP on BMSC differentiation and osteoclasts maturation in GIOP were investigated in vivo and in vitro. The immunostaining of osterix (OSX) and tartrateresistant acid phosphatase (TRAP) staining indicated that TMP promoted osteogenesis and inhibited osteoclastogenesis in a rat model of GIOP. Treatment with 106 M dexamethasone (Dex) significantly inhibited BMSC differentiation and increased TRAPpositive cells in vitro. However, different concentrations of TMP (50, 100 and 200 µM) ameliorated the negative effects of Dex by promoting the activity of alkaline phosphatase (ALP) and the calcium mineralization of BMSCs following osteogenic induction, which increased the expression levels of osteogenic genes, including ALP, collagen type I α1, osteocalcin and OSX, and decreased osteoclastogenesisrelated genes, including TRAP, nuclear factor of Tcells cytoplasmic 1 and cathepsin K. In addition, it was found that the inhibition of receptor activator of nuclear factorκB ligand and intereleukin6 in BMSCs may be a possible mechanism for the protective effects of TMP against glucocorticoidinduced osteoclastogenesis. These results are the first, to the best of our knowledge, to demonstrate that TMP promotes BMSC differentiation and inhibits osteoclastogenesis to ameliorate bone mass change in GIOP.
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Diferenciación Celular/efectos de los fármacos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoclastos/citología , Osteogénesis/efectos de los fármacos , Pirazinas/farmacología , Animales , Resorción Ósea , Huesos/diagnóstico por imagen , Huesos/metabolismo , Femenino , Interleucina-6/genética , Interleucina-6/metabolismo , Osteoclastos/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , Ratas , Tomografía Computarizada por Rayos XRESUMEN
Postmenopausal osteoporosis is one of the most prominent worldwide public health problems and the morbidity is increasing with the aging population. It has been demonstrated that early diagnosis and intervention delay the disease progression and improve the outcome. Therefore, searching for biomarkers that are able to identify postmenopausal women at high risk for developing osteoporosis is an effective way to improve the quality of life of patients, and alleviate social and economic burdens. In the present study, a protein array was used to identify potential biomarkers. The bone mineral densities of 10 rats were dynamically measured in an ovariectomized model by microcomputed tomography assessment, and the early stage of osteoporosis was defined. Through the protein arraybased screening, the expression levels of six serum protein biomarkers in ovariectomized rats were observed to alter at the initiation stage of the postmenopausal osteoporosis. Fractalkine, tissue inhibitor of metalloproteinases1 and monocyte chemotactic protein1 were finally demonstrated to be increased in the serum of eight enrolled postmenopausal osteoporosis patients using ELISA assay and were correlated with the severity of progressive bone loss. These biomarkers may be explored as potential early biomarkers to readily evaluate and diagnose postmenopausal osteoporosis in the clinic.
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Proteínas Sanguíneas , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/diagnóstico , Anciano , Animales , Biomarcadores , Diagnóstico Precoz , Femenino , Humanos , Persona de Mediana Edad , Modelos Animales , Ovariectomía/efectos adversos , Análisis por Matrices de Proteínas , Ratas , Reproducibilidad de los Resultados , Microtomografía por Rayos XRESUMEN
Bone cancer pain has been reported to have unique mechanisms and is resistant to morphine treatment. Recent studies have indicated that neuron-restrictive silencer factor (NRSF) plays a crucial role in modulating the expression of the µ-opioid receptor (MOR) gene. The present study elucidates the regulatory mechanisms of MOR and its ability to affect bone cancer pain. Using a sarcoma-inoculated murine model, pain behaviors that represent continuous or breakthrough pain were evaluated. Expression of NRSF in the dorsal root ganglion (DRG) and spinal dorsal horn was quantified at the transcriptional and translational levels, respectively. Additionally, chromatin immunoprecipitation assays were used to detect NRSF binding to the promoter of MOR. Furthermore, NRSF was genetically knocked out by antisense oligodeoxynucleotide, and the expression of MOR and the effect of morphine were subsequently analyzed. Our results indicated that in a sarcoma murine model, NRSF expression is upregulated in dorsal root ganglion neurons, and the expression of NRSF mRNA is significantly negatively correlated with MOR mRNA expression. Additionally, chromatin immunoprecipitation analysis revealed that NRSF binding to the neuron-restrictive silencer element within the promoter area of the MOR gene is promoted with a hypoacetylation state of histone H3 and H4. Furthermore, genetically knocking down NRSF with antisense oligodeoxynucleotide rescued the expression of MOR and potentiated the systemic morphine analgesia. The present results suggest that in sarcoma-induced bone cancer pain, NRSF-induced downregulation of MOR is involved in the reduction of morphine analgesia. Epigenetically, up-regulation of MOR could substantially improve the effect of system delivery of morphine.
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Analgésicos Opioides/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Regulación hacia Abajo/fisiología , Morfina/uso terapéutico , Receptores Opioides mu/metabolismo , Proteínas Represoras/metabolismo , Sarcoma/complicaciones , Analgésicos Opioides/química , Animales , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Dolor en Cáncer/etiología , Dolor en Cáncer/patología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Ganglios Espinales/patología , Histonas/metabolismo , Masculino , Ratones , Morfina/química , Actividad Motora , Oligodesoxirribonucleótidos Antisentido/farmacología , Dimensión del Dolor , ARN Mensajero/metabolismo , Receptores Opioides mu/genética , Proteínas Represoras/genética , Sarcoma/diagnóstico por imagen , Sarcoma/patología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/fisiología , Médula Espinal/patología , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: Symptomatic cervical disc disease (SCDD) is a common degenerative disease, and Discover artificial cervical disc, a new-generation nonconstrained artificial disk, has been developed and performed gradually to treat it. We performed this meta-analysis to compare the efficacy and safety between Discover cervical disc arthroplasty (DCDA) and anterior cervical discectomy and fusion (ACDF) for SCDD. METHODS: An exhaustive literature search of PubMed, EMBASE, and the Cochrane Library was conducted to identify randomized controlled trials that compared DCDA with ACDF for patients suffering SCDD. A random-effect model was used. Results were reported as standardized mean difference or risk ratio with 95% confidence interval. RESULTS: Of 33 articles identified, six studies were included. Compared with ACDF, DCDA demonstrated shorter operation time (P < 0.0001), and better range of motion (ROM) at the operative level (P < 0.00001). But no significant differences were observed in blood loss, neck disability index (NDI) scores, neck and arm pain scores, Japanese orthopaedic association (JOA) scores, secondary surgery procedures and adverse events (P > 0.05). Subgroup analyses did not demonstrated significant differences. CONCLUSION: In conclusion, DCDA presented shorter operation time, and better ROM at the operative level. However, no significant differences were observed in blood loss, NDI scores, neck and arm pain scores, JOA scores, secondary surgery procedures and adverse events between the two groups. Additionally, more studies of high quality with mid- to long-term follow-up are required in future.
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Degeneración del Disco Intervertebral/cirugía , Desplazamiento del Disco Intervertebral/cirugía , Adulto , Vértebras Cervicales/cirugía , Discectomía , Femenino , Humanos , Disco Intervertebral/cirugía , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Rango del Movimiento Articular , Resultado del TratamientoRESUMEN
The molecular mechanisms of intervertebral disc degeneration (IDD) remain elusive. We found that miR-155 is down-regulated in degenerative nucleus pulposus (NP), and more severe degeneration is correlated with higher matrix metallopeptidase 16 (MMP-16) expression. MMP-16 also degraded matrix aggrecan. Here, we addressed the in vivo miR-155-mediated pathological impact on IDD using a classic puncture mouse model. Lentiviral upregulated-miR-155 or downregulated-miR-155 was transduced into the discs of C57 mice, which was validated by real-time polymerase chain reaction (real-time PCR) and in situ hybridization. Immunohistochemistry and western blotting revealed that up-regulation of miR-155 resulted in down-regulation of MMP-16 and an increase in aggrecan and collagen type II in mouse NP; whereas, down-regulation of miR-155 resulted in up-regulation of MMP-16 and a decrease in aggrecan in mouse NP. Radiographic and histological analysis showed that the up-regulation of miR-155 attenuated IDD, while down-regulation of miR-155 resulted in the deterioration of IDD. These findings indicate that decreased miR-155 contributed to the up-regulation of MMP-16 in vivo, and MMP-16 further degraded aggrecan and collagen type II, leading to the dehydration and degeneration of discs. Our findings revealed a therapeutic role for miR-155 in IDD. © 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:1323-1334, 2017.
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Degeneración del Disco Intervertebral/etiología , Metaloproteinasa 16 de la Matriz/metabolismo , MicroARNs/metabolismo , Regiones no Traducidas 3' , Adulto , Anciano , Agrecanos/biosíntesis , Animales , Colágeno Tipo II/metabolismo , Humanos , Disco Intervertebral/patología , Degeneración del Disco Intervertebral/enzimología , Degeneración del Disco Intervertebral/patología , Lentivirus , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Persona de Mediana Edad , Adulto JovenRESUMEN
Glucocorticoid-induced osteoporosis (GIOP) is a widespread clinical complication due to the common use of glucocorticoids. Excess glucocorticoids induce apoptosis of bone marrow-derived mesenchymal stem cells (BMSCs), which have been shown to play an increasingly important role in the pathogenesis and therapy of osteoporosis. Tetramethylpyrazine (TMP), an extract from one of the most recognized herbs in traditional Chinese medicine (Chuanxiong), has been reported to have antiapoptotic properties. In this study, we tested whether TMP protects rat BMSCs following exposure to glucocorticoids in vitro and in vivo. We treated BMSCs with different concentrations of TMP (50, 100, or 200 µM) and exposed them to 10-6 M dexamethasone (Dex) for 48 h in vitro. Our data showed that TMP inhibited Dex-induced cytotoxicity and protected BMSCs from apoptosis. Interestingly, further results demonstrated that TMP prevented apoptosis in BMSCs by promoting autophagy in an AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathway-dependent manner. In addition, calcein fluorescence double labeling and microcomputed tomography scanning indicated that 12 weeks of TMP administration augmented bone formation and protected trabecular bone mass in GIOP rats. We also discovered that first-passage BMSCs isolated from the TMP treatment group had a lower rate of apoptosis and a higher light chain 3 (LC3)-II/LC3-I ratio than the GIOP group. Our findings demonstrate for the first time that TMP can protect BMSCs from exposure to excess glucocorticoids by promoting autophagy through AMPK/mTOR pathway and might be an effective agent for the prevention and treatment of GIOP.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Huesos/patología , Glucocorticoides/efectos adversos , Células Madre Mesenquimatosas/citología , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Pirazinas/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Huesos/efectos de los fármacos , Dexametasona , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteoporosis/patología , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Pirazinas/farmacología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Neuropathic pain is considered as one of the most difficult types of pain to manage with conventional analgesics. EGb-761 is extracted from leaves of Ginkgo biloba and has analgesia and anti-inflammatory properties. This study aimed to examine the effect of EGb-761 on chronic constriction injury (CCI)-induced neuropathic pain behaviors, including thermal hyperalgesia and mechanical allodynia, and to explore the possible mechanisms underlying this action. To this end, CCI mice were intraperitoneally injected with EGb-761 (10, 20, 40, and 80 mg/kg), and thermal hyperalgesia, mechanical allodynia, cytokines, and mu-opioid receptor expression were measured. Results showed that EGb-761 attenuated thermal hyperalgesia and mechanical allodynia dose-dependently and the best delivery time window was from day 7 to day 14 after CCI. Additionally, EGb-761 treatment significantly decreased pro-inflammatory cytokines and enhanced mu opioid receptor (MOR) expression in the sciatic nerve. Moreover, the opioid antagonist naloxone prevented the effect of EGb-761 on thermal hyperalgesia and mechanical allodynia but did not influence the effect of EGb-761 on inflammatory cytokines. In conclusion, this study suggests that the potential of EGb-761 as a new analgesic for neuropathic pain treatment, and opioid system may be involved in the EGb-761-induced attenuation of thermal hyperalgesia and mechanical allodynia. Copyright © 2016 John Wiley & Sons, Ltd.
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Analgésicos Opioides/química , Ginkgo biloba/química , Neuralgia/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Masculino , Ratones , Extractos Vegetales/farmacología , Ratas Sprague-DawleyRESUMEN
Free fatty acids display diverse effects as signalling molecules through GPCRs in addition to their involvement in cellular metabolism. GPR120, a G protein-coupled receptor for long-chain unsaturated fatty acids, has been reported to mediate adipogenesis in lipid metabolism. However, whether GPR120 also mediates osteogenesis and regulates BMMSCs remain unclear. In this study, we showed that GPR120 targeted the bi-potential differentiation of BMMSCs in a ligand dose-dependent manner. High concentrations of TUG-891 (a highly selective agonist of GPR120) promoted osteogenesis via the Ras-ERK1/2 cascade, while low concentrations elevated P38 and increased adipogenesis. The fine molecular regulation of GPR120 was implemented by up-regulating different integrin subunits (α1, α2 and ß1; α5 and ß3). The administration of high doses of TUG-891 rescued oestrogen-deficient bone loss in vivo, further supporting an essential role of GPR120 in bone metabolism. Our findings, for the first time, showed that GPR120-mediated cellular signalling determines the bi-potential differentiation of BMMSCs in a dose-dependent manner. Additionally, the induction of different integrin subunits was involved in the cytoplasmic regulation of a seesaw-like balance between ERK and p38 phosphorylation. These findings provide new hope for developing novel remedies to treat osteoporosis by adjusting the GPR120-mediated differentiation balance of BMMSCs.
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Células de la Médula Ósea/citología , Diferenciación Celular , Células Madre Mesenquimatosas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adipogénesis/efectos de los fármacos , Animales , Compuestos de Bifenilo/farmacología , Huesos/química , Huesos/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Integrinas/metabolismo , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Osteogénesis/efectos de los fármacos , Fenilpropionatos/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/efectos de los fármacos , Proteínas ras/metabolismoRESUMEN
BACKGROUND: Giant cell tumor of bone (GCT) is a potentially malignant tumor. CD147 is a multifunctional protein, which expresses itself in many tumors. In this study, we have investigated the correlation between CD147 and PCNA, VEGF, MMPs expression in giant cell tumor of bones. We have also explored the relationship between its clinical pathology and prognosis. RESULTS: A significant difference of the expression level of CD147, MMPs was found in cases of GCT with Jaffe grading and prognosis (P<0.05). But, it was not in accordance with the patient's age and sex. An expression of CD147 was positively correlated with MMP-9, VEGF, MVD, PCNA (r=0.271, P=0.025; r=0.411, P=0.000; r=0.872, P=0.000; r=0.394, P=0.001). CONCLUSION: The expression level of CD147 in giant cell tumors of bones is correlated with the development of cancers and relapse. There was a positive correlation between expressions of CD147 and MMP-9, VEGF, MVD, PCNA, and CD147. This is an important indicator in evaluating the malignant degree and prognosis of giant cell tumors of bone. It may be the new target for ensuring chemopreventive strategies.