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BACKGROUND: Nucleus pulposus cell (NPC) senescence in intervertebral disc (IVD) tissue is the major pathological cause of intervertebral disc degeneration (IDD). N6-methyladenosine (m6A) methylation and gut microbiota play important roles in the progression of IDD. This study investigated whether methyltransferase-like 3 (METTL3) regulates TLR2 m6A modification and gut microbiota to influence NPC senescence. METHODS: An IDD rat model was established by lumbar IVD puncture and NPCs were challenged with IL-1ß to mimic IVD injury. IDD rats and IL-1ß-exposed NPCs were treated with METTL3-interfering lentivirus and the TLR2 agonist Pam3CSK4. Compositional changes in the rat gut microbiota were analyzed and fecal microbiota transplantation procedures were used. NPC senescence, cell cycle, and the expression of senescence-associated secretory phenotype (SASP) factors were assessed. The m6A enrichment of TLR2 and the binding of IGF2BP1 to TLR2 mRNA were examined. RESULTS: METTL3 and TLR2 were highly expressed in IDD rats. METTL3 silencing attenuated senescent phenotypes and reduced secretion of SASP factors. Pam3CSK4 reversed the beneficial effects of METTL3 silencing on NPC senescence and IVD injury. METTL3 stabilized TLR2 mRNA in an IGF2BP1-dependent manner. METTL3 silencing restored specific gut microbiota levels in IDD rats, which was further reversed by administration of Pam3CSK4. Fecal microbiota from METTL3 silenced IDD rats altered the pathological phenotypes of IDD rats. CONCLUSIONS: These results demonstrate the beneficial effects of METTL3 silencing on NPC senescence and amelioration of IVD injury, involving modulation of TLR2 m6A modification and gut microbiota. These findings support METTL3 silencing as a potential therapeutic target for IDD.
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Senescencia Celular , Microbioma Gastrointestinal , Degeneración del Disco Intervertebral , Metiltransferasas , Núcleo Pulposo , Ratas Sprague-Dawley , Receptor Toll-Like 2 , Animales , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Ratas , Metiltransferasas/metabolismo , Metiltransferasas/genética , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patología , Degeneración del Disco Intervertebral/metabolismo , Degeneración del Disco Intervertebral/patología , Degeneración del Disco Intervertebral/microbiología , Masculino , Modelos Animales de Enfermedad , Metilación , Adenosina/análogos & derivados , Adenosina/metabolismoRESUMEN
Endplate sclerosis is a notable aspect of spine degeneration or aging, but the mechanisms remain unclear. Here, we report that senescent macrophages accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging male mouse model. Specifically, knockout of cdkn2a (p16) in macrophages abrogates LSI or aging-induced angiogenesis and sclerosis in the endplates. Furthermore, both in vivo and in vitro studies indicate that IL-10 is the primary elevated cytokine of senescence-related secretory phenotype (SASP). Mechanistically, IL-10 increases pSTAT3 in endothelial cells, leading to pSTAT3 directly binding to the promoters of Vegfa, Mmp2, and Pdgfb to encourage their production, resulting in angiogenesis. This study provides information on understanding the link between immune senescence and endplate sclerosis, which might be useful for therapeutic approaches.
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Senescencia Celular , Interleucina-10 , Animales , Masculino , Ratones , Angiogénesis , Células Endoteliales , Interleucina-10/genética , Macrófagos , EsclerosisRESUMEN
To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.
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Antígenos Nucleares , Microbioma Gastrointestinal , Proteína Quinasa 1 Activada por Mitógenos , Proteínas del Tejido Nervioso , Neuralgia , Ratas Sprague-Dawley , Triterpenos , Ácido Ursólico , Animales , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Triterpenos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Simulación del Acoplamiento Molecular , Modelos Animales de Enfermedad , Nervios Espinales/efectos de los fármacos , Analgésicos/farmacología , Colon/efectos de los fármacos , Colon/microbiología , Colon/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismoRESUMEN
Low back pain (LBP) is one of the most prevalent diseases affecting quality of life, with no disease-modifying therapy. During aging and spinal degeneration, the balance between the normal endplate (EP) bilayers of cartilage and bone shifts to more bone. The aged/degenerated bony EP has increased porosity because of osteoclastic remodeling activity and may be a source of LBP due to aberrant sensory innervation within the pores. We used two mouse models of spinal degeneration to show that parathyroid hormone (PTH) treatment induced osteogenesis and angiogenesis and reduced the porosity of bony EPs. PTH increased the cartilaginous volume and improved the mechanical properties of EPs, which was accompanied by a reduction of the inflammatory factors cyclooxygenase-2 and prostaglandin E2. PTH treatment furthermore partially reversed the innervation of porous EPs and reversed LBP-related behaviors. Conditional knockout of PTH 1 receptors in the nucleus pulposus (NP) did not abolish the treatment effects of PTH, suggesting that the NP is not the primary source of LBP in our mouse models. Last, we showed that aged rhesus macaques with spontaneous spinal degeneration also had decreased EP porosity and sensory innervation when treated with PTH, demonstrating a similar mechanism of PTH action on EP sclerosis between mice and macaques. In summary, our results suggest that PTH treatment could partially reverse EP restructuring during spinal regeneration and support further investigation into this potentially disease-modifying treatment strategy for LBP.
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Dolor de la Región Lumbar , Hormona Paratiroidea , Ratones , Animales , Hormona Paratiroidea/farmacología , Hormona Paratiroidea/uso terapéutico , Macaca mulatta , Calidad de Vida , Modelos Animales de EnfermedadRESUMEN
The m6A methylation is reported to function in multiple physiological and pathological processes. However, the functional relevance of m6A modification to post-spinal cord injured (SCI) damage is not yet clear. In the present study, methylated RNA immunoprecipitation combined with microarray analysis showed that the global RNA m6A levels were decreased following SCI. Then, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted to demonstrate the potential function of differential m6A-tagged transcripts and the altered transcripts with differential m6A levels. In addition, we found that the m6A "writer," METTL3, significantly decreased after SCI in mice. The immunostaining validated that the expression of METTL3 mainly changed in GFAP or Iba-1+ cells. Together, this study shows the alteration of m6A modification following SCI in mice, which might contribute to the pathophysiology of the spinal cord after trauma.
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PURPOSE: VBT is a novel alternative to spinal fusion surgery to treat skeletally immature AIS and was approved to correct idiopathic scoliosis in August 2019 by US Federal Drug Administration (FDA). To systemically review the preliminary outcomes of vertebral body tethering (VBT) in treating adolescent idiopathic scoliosis. METHODS: The electronic databases PubMed, EMBASE, and Web of Science were queried up to January 2022 for articles regarding VBT. Basic characteristics of patients, changes of radiographic parameters in coronal and sagittal planes, and clinical outcomes of surgical treatment of VBT including complication and revision rates were summarized. RESULTS: Twenty five studies met the inclusion criteria. Most studies (23/25) included patients with only skeletal immaturity. The average % correction of the main/tethered curve at final follow-up, and % correction of thoracic kyphosis at final follow-up were reported to be 15.6-106.5% and - 31.8 to 20.0%, respectively. The most common complications for VBT were tether breakage (n = 145;21.3%), pulmonary complications (n = 49; 6.9%), and overcorrection (n = 30; 4.2%). The revision rate was 13.1%. CONCLUSION: VBT could effectively and safely correct spinal deformity in skeletally immature patients with AIS and preserve the motion and growth of the spine. However, VBT has a relatively high complication and revision rates. Therefore, surgeons should cautiously consider VBT for treating AIS. Future research efforts are needed to lower the complication and revision rates. Whatever, VBT is still in its infancy and may have a promising future as a non-fusion solution for AIS.
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Cifosis , Escoliosis , Humanos , Adolescente , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Cuerpo Vertebral , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Resultado del TratamientoRESUMEN
Mechanical force regulates bone density, modeling, and homeostasis. Substantial periosteal bone formation is generated by external mechanical stimuli, yet its mechanism is poorly understood. Here, it is shown that myeloid-lineage cells differentiate into subgroups and regulate periosteal bone formation in response to mechanical loading. Mechanical loading on tibiae significantly increases the number of periosteal myeloid-lineage cells and the levels of active transforming growth factor ß (TGF-ß), resulting in cortical bone formation. Knockout of Tgfb1 in myeloid-lineage cells attenuates mechanical loading-induced periosteal bone formation in mice. Moreover, CD68+ F4/80+ macrophages, a subtype of myeloid-lineage cells, express and activate TGF-ß1 for recruitment of osteoprogenitors. Particularly, mechanical loading induces the differentiation of periosteal CD68+ F4/80- myeloid-lineage cells to the CD68+ F4/80+ macrophages via signaling of piezo-type mechanosensitive ion channel component 1 (Piezo1) for TGF-ß1 secretion. Importantly, CD68+ F4/80+ macrophages activate TGF-ß1 by expression and secretion of thrombospondin-1 (Thbs1). Administration of Thbs1 inhibitor significantly impairs loading-induced TGF-ß activation and recruitment of osteoprogenitors in the periosteum. The results suggest that periosteal myeloid-lineage cells respond to mechanical forces and consequently produce and activate TGF-ß1 for periosteal bone formation.
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Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno B7-1/metabolismo , Hueso Cortical/metabolismo , Osteogénesis/fisiología , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Periostio/metabolismo , Transducción de Señal/fisiologíaRESUMEN
We used NHANES data to explore the association between dietary quality estimated by the HEI-2015 and osteoporosis in middle-aged and elderly US adults. We found that higher dietary quality is significantly associated with a reduced risk of osteoporosis among middle-aged and elderly Americans. INTRODUCTION: Through this research, we assess whether increasing the overall dietary quality reduces the risk of osteoporosis. METHODS: For our analyses, we combined data collected from four NHANES 2-year cycles (2007-2008, 2009-2010, 2013-2014, and 2017-2018), including 10,033 participants. Associations between osteoporosis and HEI-2015 total/component scores among middle-aged and elderly adults were examined using logistic regression models. Osteoporosis was defined as femur neck BMD values equal to or less than 2.5 standard deviations (SDs) below the mean of the young adult reference group, and dietary intake data were obtained from two NHANES 24-h recall interviews. RESULTS: After multivariable adjustment, middle-aged and elderly populations with quintile 4 (OR: 0.54, 95% CI 0.34, 0.84; P = 0.007) and quintile 5 HEI-2015 total scores (OR: 0.43, 95% CI 0.26, 0.70; P = 0.001) were associated with reduced odds of osteoporosis compared with quintile 1. Higher intake of total vegetables, greens and beans, total fruits, whole fruits, and whole grains was associated with decreased odds of osteoporosis among elderly adults. Surprisingly, saturated fat intake can also protect against osteoporosis. CONCLUSION: Higher dietary quality estimated from HEI-2015 total and component food scores was significantly associated with a reduced risk of osteoporosis among the middle-aged and elderly Americans participating in NHANES included in this study.
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Dieta Saludable , Osteoporosis , Anciano , Estudios Transversales , Dieta , Humanos , Persona de Mediana Edad , Encuestas Nutricionales , Osteoporosis/epidemiología , Osteoporosis/etiología , Osteoporosis/prevención & control , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Some studies have suggested an association between serum copper and bone density. Few studies have explored the association between copper intake and osteoporosis and bone mineral density (BMD). Our research aims to assess the associations of copper intake with the risk of osteoporosis in United States adults using the National Health and Nutritional Examination Surveys (NHANES). A total of 8224 individuals were included in our study. Osteoporosis was defined that BMD values surpass 2.5 standard deviations (SD) below the mean of the young adult reference group. Copper intake from diets and supplements was estimated by using two 24-h recall surveys. After adjustment for all the covariates of interest, the odds ratios (ORs) (95% confidence interval (CI)) between the risk of osteoporosis and total copper intake across quartiles 3 and 4 compared with quartile 1 were 0.48 (0.31-0.74) (P < 0.01) and 0.41 (0.26-0.65) (P < 0.01), respectively. The mean total femur BMD and total spine BMD of the highest dietary copper intake quartile (Cu 1.51 mg/d) was 0.03 g/cm2 and 0.02 g/cm2 greater than the lowest quartile. Our results indicate that dietary and total copper intake was positively associated with increasing BMD in US adults and negatively associated with the risk of osteoporosis in US adults.
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Densidad Ósea , Osteoporosis , Absorciometría de Fotón/métodos , Cobre , Humanos , Encuestas Nutricionales , Osteoporosis/epidemiología , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Acute spinal cord injury (ASCI) is a severe traumatic disease of the central nervous system, the underlying mechanism of which is unclear. This study was intended to study the role of EZH2 and miR-146a-5p/HIF-1α in inflammation and glycolysis after ASCI, providing reference and basis for the clinical treatment and prognosis of ASCI injury. We used lipopolysaccharide (LPS) to induce inflammation of microglia, and we constructed the ASCI animal model. qRT-PCR detected the relative expression levels of EZH2, HIF-1α, miR-146a-5p, IL-6, TNF-α, IL-17, PKM2, GLUT1, and HK2 in cells and tissues. Western blot was performed to detect the expression levels of EZH2, HIF-1α, H3K27me3, IL-6, TNF-α, IL-17, PKM2, GLUT1, and HK2. ChIP verified the enrichment of H3K27me3 in the miR-146a-5p promoter region. Bioinformatics predicted the binding sites of HIF-1α and miR-146a-5p, and dual-luciferase reporter assay verified the binding of HIF-1α and miR-146a-5p. ELISA detects the levels of inflammatory factors IL-6, TNF-α, and IL-17 in the cerebrospinal fluid of rats. The GC-TOFMS was used to detect the changes of glycolytic metabolites in the cerebrospinal fluid of rats. EZH2 could mediate inflammation and glycolysis of microglia. EZH2 regulates inflammation and glycolysis through HIF-1α. EZH2 indirectly regulated the HIF-1α expression by mediating miR-146a-5p. EZH2 mediates miR-146a-5p/HIF-1α to alleviate inflammation and glycolysis in ASCI rats. In the present study, our results demonstrated that EZH2 could mediate miR-146a-5p/HIF-1α to alleviate the inflammation and glycolysis after ASCI. Therefore, EZH2/miR-146a-5p/HIF-1α might be a novel potential target for treating ASCI.
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Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación de la Expresión Génica , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/metabolismo , MicroARNs/metabolismo , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Metabolómica , Microglía/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety-related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX-/- mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element-binding protein (pCREB), and brain-derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment-enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL-1ß, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol-mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX-/- mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety-related behaviors. This study provides that resveratrol-mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery-induced LBP and hippocampus-related anxiety.
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Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Dolor de la Región Lumbar/tratamiento farmacológico , Osteogénesis/efectos de los fármacos , Resveratrol/farmacología , Sirtuina 1/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Ansiedad/metabolismo , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Dolor de la Región Lumbar/metabolismo , Masculino , Ratones Endogámicos C57BL , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismoRESUMEN
Exploring the three-dimensional (3D) morphology of neurons is essential to understanding spinal cord function and associated diseases comprehensively. However, 3D imaging of the neuronal network in the broad region of the spinal cord at cellular resolution remains a challenge in the field of neuroscience. In this study, to obtain high-resolution 3D imaging of a detailed neuronal network in the mass of the spinal cord, the combination of synchrotron radiation micro-computed tomography (SRµCT) and the Golgi-cox staining were used. We optimized the Golgi-Cox method (GCM) and developed a modified GCM (M-GCM), which improved background staining, reduced the number of artefacts, and diminished the impact of incomplete vasculature compared to the current GCM. Moreover, we achieved high-resolution 3D imaging of the detailed neuronal network in the spinal cord through the combination of SRµCT and M-GCM. Our results showed that the M-GCM increased the contrast between the neuronal structure and its surrounding extracellular matrix. Compared to the GCM, the M-GCM also diminished the impact of the artefacts and incomplete vasculature on the 3D image. Additionally, the 3D neuronal architecture was successfully quantified using a combination of SRµCT and M-GCM. The SRµCT was shown to be a valuable non-destructive tool for 3D visualization of the neuronal network in the broad 3D region of the spinal cord. Such a combinatorial method will, therefore, transform the presentation of Golgi staining from 2 to 3D, providing significant improvements in the 3D rendering of the neuronal network.
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Aparato de Golgi/química , Imagenología Tridimensional , Neuronas/citología , Médula Espinal/citología , Coloración y Etiquetado , Microtomografía por Rayos X , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , SincrotronesRESUMEN
AIM: Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. While early proactive management is crucial in alleviating symptoms in OA patients, currently available therapeutic approaches are yet to achieve an ideal level of efficacy. The path to the development of a potent treatment begins with the thorough understanding of the pathophysiology of OA. The present study aims to explore the mechanism by which SGK1 is involved in OA progression. METHODS: Firstly, the potential target gene of SGK1 was screened and SGK1 expression was determined in OA through bioinformatics analysis. Mouse OA model was then established and chondrocytes were extracted, after which inflammation was induced with lipopolysaccharide (LPS). Following LPS treatment, the chondrocytes were transfected with synthesized plasmids to explore the impact of SGK1, CREB1, and ABCA1 on apoptosis, proliferation and inflammation in OA. ChIP-PCR and dual-luciferase reporter gene assay were conducted to determine the binding relation between SGK1 and CREB1 as well as between CREB1 and ABCA1. RESULTS: OA mice presented with high expression of SGK1. Interestingly, we found that SGK1 inhibited CREB1 expression in chondrocytes, thereby inducing inflammation and suppressing chondrocyte proliferation. CREB1 was found to have a positive correlation with ABCA1 expression, while down-regulation of CREB1 resulted in the inhibition of cell proliferation and aggravated inflammation, which could be reversed by overexpressed ABCA1. CONCLUSION: Taken altogether, silencing of SGK1 alleviated OA through epigenetic regulation of CREB1 and ABCA1 expression. These findings may provide novel insight into SGK1-based strategy for OA treatment.
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Transportador 1 de Casete de Unión a ATP/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Epigénesis Genética , Proteínas Inmediatas-Precoces/genética , Osteoartritis/genética , Proteínas Serina-Treonina Quinasas/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Apoptosis/genética , Cartílago Articular/patología , Proliferación Celular/genética , Condrocitos/efectos de los fármacos , Condrocitos/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Silenciador del Gen , Proteínas Inmediatas-Precoces/metabolismo , Lipopolisacáridos/toxicidad , Masculino , Ratones Endogámicos C57BL , Osteoartritis/fisiopatología , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
The complex pathology of chronic thoracic spinal cord compression involves vascular and neuroarchitectural repair processes that are still largely unknown. In this study, we used synchrotron radiation microtomography (SRµCT) to quantitatively characterize the 3D temporal-spatial changes in the vascular and neuronal network after chronic thoracic spinal cord compression in order to obtain further insights into the pathogenesis of this disease and to elucidate its underlying mechanisms. Direct 3D characterization of the spinal cord microvasculature and neural microstructure of the thoracic spinal cord was successfully reconstructed. The significant reduction in vasculature and degeneration of neurons in the thoracic spinal cord visualized via SRµCT after chronic compression were consistent with the changes detected by immunofluorescence staining. The 3D morphological measurements revealed significant reductions of neurovascular parameters in the thoracic spinal cord after 1 month of compression and became even worse after 6 months without relief of compression. In addition, the distinct 3D morphological twist and the decrease in branches of the central sulcal artery after chronic compression vividly displayed that these could be the potential triggers leading to blood flow reduction and neural deficits of the thoracic spinal cord. Our findings propose a novel methodology for the 3D analysis of neurovascular repair in chronic spinal cord compression, both qualitatively and quantitatively. The results indicated that compression simultaneously caused vascular dysfunction and neuronal network impairment, which should be acknowledged as concurrent events after chronic thoracic spinal cord injury. Combining neuroprotection with vasoprotection may provide promising therapeutic targets for chronic thoracic spinal cord compression.
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The sensory nerve was recently identified as being involved in regulation of bone mass accrual. We previously discovered that prostaglandin E2 (PGE2) secreted by osteoblasts could activate sensory nerve EP4 receptor to promote bone formation by inhibiting sympathetic activity. However, the fundamental units of bone formation are active osteoblasts, which originate from mesenchymal stromal/stem cells (MSCs). Here, we found that after sensory denervation, knockout of the EP4 receptor in sensory nerves, or knockout of COX-2 in osteoblasts, could significantly promote adipogenesis and inhibit osteogenesis in adult mice. Furthermore, injection of SW033291 (a small molecule that locally increases the PGE2 level) or propranolol (a beta blocker) significantly promoted osteogenesis and inhibited adipogenesis. This effect of SW033291, but not propranolol, was abolished in conditional EP4-KO mice under normal conditions or in the bone repair process. We conclude that the PGE2/EP4 sensory nerve axis could regulate MSC differentiation in bone marrow of adult mice.
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Adipogénesis , Dinoprostona/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteogénesis , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Células Receptoras Sensoriales/metabolismo , Animales , Ciclooxigenasa 2/metabolismo , Dinoprostona/genética , Técnicas de Inactivación de Genes , Células Madre Mesenquimatosas/patología , Ratones , Ratones Noqueados , Osteoblastos/metabolismo , Osteoblastos/patología , Subtipo EP4 de Receptores de Prostaglandina E/genética , Células Receptoras Sensoriales/patologíaRESUMEN
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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Objectives: To investigate the association of sedentary behavior with anxiety, depression, and suicide ideation in multi-centered college students in China. Methods: This was a cross-sectional study of the first-year college student population. The students underwent a questionnaire survey inquiring about sedentary behavior (hours per day) and physical activity (minutes per week) during the past year. Anxiety, depression, and sleep quality were measured by the Generalized Anxiety Disorder Scale (GAD-2), the Patient Health Questionnaire (PHQ-2), and the Pittsburgh Sleep Quality Index (PSQI), respectively. Mixed models were used to estimate the associations, and adjusted odds ratios (AORs) were presented as the effect size. Mediation effect analysis was conducted to test the mediation effect of PSQI. Results: A total of 28,298 participants (response rate: 82%) completed the survey and were included in the final analyses. Crude and adjusted estimates consistently showed that both sedentary behavior and physical activity were significantly associated with mental illnesses. Sedentary behavior was positively associated with anxiety, depression, and suicidal behavior in a dose-response manner (AOR: 0.54-0.24; ≥7 h/day as reference), independent from the effect of physical activity (AOR: 0.78-0.41; no physical activity as reference). The association of sedentary behavior with mental health was partly mediated by sleep quality (25-71%). Conclusions: There is an independent dose-response association of sedentary behavior with mental well-being among college students in China, and this association may be partially attributable to impaired sleep quality. Attention should be drawn and actions should be taken by college educators and mental health providers.
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Spinal pain is a major clinical problem, however, its origins and underlying mechanisms remain unclear. Here we report that in mice, osteoclasts induce sensory innervation in the porous endplates which contributes to spinal hypersensitivity in mice. Sensory innervation of the porous areas of sclerotic endplates in mice was confirmed. Lumbar spine instability (LSI), or aging, induces spinal hypersensitivity in mice. In these conditions, we show that there are elevated levels of PGE2 which activate sensory nerves, leading to sodium influx through Nav 1.8 channels. We show that knockout of PGE2 receptor 4 in sensory nerves significantly reduces spinal hypersensitivity. Inhibition of osteoclast formation by knockout Rankl in the osteocytes significantly inhibits LSI-induced porosity of endplates, sensory innervation, and spinal hypersensitivity. Knockout of Netrin-1 in osteoclasts abrogates sensory innervation into porous endplates and spinal hypersensitivity. These findings suggest that osteoclast-initiated porosity of endplates and sensory innervation are potential therapeutic targets for spinal pain.
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Hipersensibilidad/patología , Placa Motora/patología , Netrina-1/metabolismo , Osteoclastos/metabolismo , Células Receptoras Sensoriales/metabolismo , Columna Vertebral/patología , Envejecimiento/patología , Animales , Conducta Animal , Dinoprostona , Modelos Animales de Enfermedad , Humanos , Hiperalgesia/patología , Vértebras Lumbares/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Netrina-1/deficiencia , Dolor/patología , Porosidad , Transducción de SeñalRESUMEN
The regeneration of the blood vessel system post spinal cord injury (SCI) is essential for the repair of neurological function. As a significant means to regulate gene expression, epigenetic regulation of angiogenesis in SCI is still largely unknown. Here, we found that Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX), the histone H3K27 demethylase, increased significantly in endothelial cells post SCI. Knockdown of UTX can promote the migration and tube formation of endothelial cells. The specific knockout of UTX in endothelial cells enhanced angiogenesis post SCI accompanied with improved neurological function. In addition, we found regulation of UTX expression can change the level of microRNA 24 (miR-24) in vitro. The physical binding of UTX to the promotor of miR-24 was indicated by chromatin immunoprecipitation (ChIP) assay. Meanwhile, methylation sequencing of endothelial cells demonstrated that UTX could significantly decrease the level of methylation in the miR-24 promotor. Furthermore, miR-24 significantly abolished the promoting effect of UTX deletion on angiogenesis in vitro and in vivo. Finally, we predicted the potential target mRNAs of miR-24 related to angiogenesis. We indicate that UTX deletion can epigenetically promote the vascular regeneration and functional recovery post SCI by forming a regulatory network with miR-24.
Asunto(s)
Células Endoteliales/citología , Epigénesis Genética , Eliminación de Gen , Histona Demetilasas/fisiología , Regeneración , Traumatismos de la Médula Espinal/terapia , Animales , Movimiento Celular , Proliferación Celular , Metilación de ADN , Células Endoteliales/fisiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Regiones Promotoras Genéticas , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/patologíaRESUMEN
There has been increasing interest in using high-resolution micro-tomography to investigate the morphology of neurovascular networks in the central nervous system, which remain difficult to characterize due to their microscopic size as well as their delicate and complex 3D structure. Synchrotron radiation X-ray imaging, which has emerged as a cutting-edge imaging technology with a high spatial resolution, provides a novel platform for the non-destructive imaging of microvasculature networks at a sub-micrometre scale. When coupled with computed tomography, this technique allows the characterization of the 3D morphology of vasculature. The current review focuses on recent progress in developing synchrotron radiation methodology and its application in probing neurovascular networks, especially the pathological changes associated with vascular abnormalities in various model systems. Furthermore, this tool represents a powerful imaging modality that improves our understanding of the complex biological interactions between vascular function and neuronal activity in both physiological and pathological states.