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1.
Br J Neurosurg ; : 1-4, 2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31544531

RESUMO

Background: We know of five cases of cervical nerve root variants that have been reported, all of which were found during posterior cervical surgery. We reported two cases of cervical nerve root variants. One had two anomalous branches of the C7 root, is the other had a C5, C6 nerve root communication branch. Case description: A 62-year-old female presented with neck and right upper extremity pain, accompanied by hypaesthesia in her right forearm for 4 months. Preoperative X-ray film, magnetic resonance imaging (MRI) and computed tomography (CT) scan demonstrated C6-7 uncovertebral joint hyperplasia and foraminal stenosis. She underwent posterior cervical endoscopic foraminoplasty. The right C7 nerve root was observed to have two anomalous branches originated from a proximal trunk. After the surgery, the symptoms resolved. A 54-year-old female presented with radiating pain and numbness in her right arm and hand for 4 months. Preoperative MRI showed a C5/6 intervertebral disc herniation. She had hypaesthesia in radial side of her right arm and 1st-3rd fingers. Posterior cervical endoscopic foraminalplasty was performed for the patient. After decompression of the bony wall of the posterior nerve root canal, a 2-mm thick communicating nerve was observed emerging from the dura with the C6 nerve root and exiting to the caudal level. After the surgery, the symptoms resolved immediately. Conclusions: Cervical nerve root variant may be more apparent on edoscopic approaches to the cervical foraminae than at open surgery.

2.
Aging (Albany NY) ; 11(18): 7537-7552, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31525733

RESUMO

Glucocorticoids contribute to the increased incidence of secondary osteoporosis. Hydrogen sulfide (H2S) is a gasotransmitter and plays an essential role in bone metabolism. In this study, we investigated the therapeutic effects of H2S on glucocorticoid-induced osteoporosis (GIO). We found that dexamethasone (Dex) decreased serum H2S and two key H2S-generating enzymes in the bone marrow in vivo, cystathione b-synthase and cystathione g-lyase. Treatment of H2S-donor GYY4137 in rat significantly relieved the inhibitory effect of Dex on bone formation. Dex inhibited osteoblasts proliferation and osteogenic differentiation and decreased the expressions of the two H2S-generating enzymes. Further investigation showed that H2S was involved in Dex-mediated osteoblasts proliferation, differentiation, and apoptosis. Mechanistically, GYY4137 promoted osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands. In comparison, the blockage of Wnt/ß-catenin signaling pathway significantly alleviated the effect of H2S on osteoblasts. In conclusion, the restoration of H2S levels is a potential novel therapeutic approach for GIO.

3.
World Neurosurg ; 130: e915-e925, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301447

RESUMO

OBJECTIVE: To evaluate the clinical and radiographic outcomes of an anterior-only approach for the correction of severe cervical kyphotic deformities. METHODS: We performed a retrospective study of 33 consecutive patients with severe cervical kyphosis treated with an anterior cervical operation and preoperative and intraoperative skull traction. Cobb angle, kyphosis index (KI), kyphosis level, C2-7 sagittal vertical axis (SVA), and T1 slope were measured. The preoperative and postoperative Japanese Orthopedic Association (JOA) scores, visual analog scale (VAS) score for neck pain, Neck Disability Index (NDI) scores, and cervical alignment were compared. RESULTS: The mean angle of the kyphosis was 83.2 ± 20.4°. The mean Cobb angle of the operative region was 71.7 ± 18.5° preoperation, which was reduced to 10.6 ± 5.7° postoperation (mean correction, 85.2%). The mean KI was 75.1 ± 18.2 preoperation, which was reduced to 14.4 ± 9.1 postoperation (mean correction, 80.8%). The preoperative and postoperative mean C2-7 Cobb angle was 53.8 ± 16.5° and 14.7 ± 7.6°, respectively. The preoperative and postoperative mean C2-7 SVA was 3.9 ± 14.5 mm and 12.8 ± 7.3 mm, respectively. The preoperative and postoperative mean T1 slope was -9.4 ± 15.7° and 7.3 ± 13.1°, respectively. The average postoperative C2-7 Cobb angle, Cobb angle of the operative region, KI, C2-7 SVA, and T1 slope changed significantly compared with preoperative values (P < 0.05). The average postoperative JOA, VAS, and NDI scores improved significantly compared with preoperative scores (P < 0.05). CONCLUSIONS: Preoperative and intraoperative skull traction combined with anterior-only cervical operation may be a safe and effective technique for treating severe cervical kyphosis. If the postoperative correction is >80%, sufficient decompression could be achieved.

4.
World Neurosurg ; 129: e586-e593, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158541

RESUMO

BACKGROUND: The purpose of this study was to determine the number of cases needed to achieve the level of competence for percutaneous endoscopic lumbar diskectomy (PELD) via the bi-needle technique using the cumulative summation test for learning curve (LC-CUSUM). METHODS: A retrospective design was used. We included 60 patients who underwent a single-level PELD via the bi-needle technique performed by a single surgeon. The surgeon had 5 years of experience in open surgery including the transforaminal endoscopic spine system and Yeung endoscopic spine system but no experience in the bi-needle technique. Surgery success was defined as an operative time <60 minutes, and the acceptable procedure was completed within 3 times of C-arm fluoroscopies. The LC-CUSUM was used to analyze the data. RESULTS: The average operative time for PELD via the bi-needle technique was 58.3 ± 12.4 minutes. The mean operative time was 65.7 ± 12.1 minutes in the early learning period (30 cases) and 51.0 ± 7.5 minutes in the late learning period (30 cases) (P < 0.05). On the basis of the evaluation indexes of the operative time and radioactive exposure, the LC-CUSUM signaled proficiency for the bi-needle technique at the 50th-54th operation. Seven cases of complications were observed during the whole learning process, with 6 in the early period and 1 in the late period (P < 0.05). CONCLUSIONS: The novel bi-needle technique is safe and effective for PELD with appropriate patients, and the learning curve is acceptable. A substantial learning period (50-54 cases) is needed before a spine surgeon can master the bi-needle technique.

5.
Gene ; 704: 15-24, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30965128

RESUMO

OBJECTIVE: The objective of our study was to verify the hypothesis that the expression of connective tissue growth factor (CTGF/CCN2), a key molecule essential for the maintenance of nucleus pulposus (NP) matrix homeostasis, is regulated by osmolarity and intracellular calcium in NP cells. METHODS: Gene and protein expression levels of CCN2 were assessed using quantitative real-time PCR and western blot. Transfections and dual luciferase assays were performed to measure the effect of hyperosmolarity, tonicity enhancer binding protein (TonEBP) and Ca2+-calcineurin (Cn)-NFAT signaling on CCN2 promoter activity. RESULTS: Cultured in hyperosmotic media, there was a significant decrease in the levels of CCN2 promoter activity, gene and protein expression in NP cells. The JASPAR database was used to analyze the construction of human CCN2 promoter, we found conserved TonE and NFAT binding sites. We then investigated whether TonEBP controlled CCN2 expression. Forced expression of TonEBP in NP cells showed that TonEBP negatively regulated CCN2 promoter activity, while suppression of TonEBP induced CCN2 promoter activity and expression. We then examined if Ca2+-Cn-NFAT signaling participated in the regulation of CCN2 expression. Co-expression of CCN2 reporter with individual NFAT1-4 expression plasmids and/or calcineurin A/B constructs suggested this signaling pathway played a role in the regulation of CCN2expression in NP cells. CONCLUSIONS: Results of these studies illustrated that the expression of CCN2 in NP cells was regulated by the NFAT family through a signaling pathway network involving both activator (Ca2+-Cn-NFAT signaling) and suppressor (Hyperosmolarity-TonEBP) molecules.


Assuntos
Cálcio/farmacologia , Fator de Crescimento do Tecido Conjuntivo/genética , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Equilíbrio Hidroeletrolítico , Animais , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Homeostase/genética , Masculino , Fatores de Transcrição NFATC/fisiologia , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/fisiologia , Desequilíbrio Hidroeletrolítico/genética , Desequilíbrio Hidroeletrolítico/metabolismo
6.
Sleep Med Rev ; 45: 18-30, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30870662

RESUMO

This review aimed to provide a comprehensive examination of the effect of sleep restriction on metabolism-related parameters by synthesizing the emerging, best evidence. A systematic search was conducted in six electronic databases from inception to January 2018. We identified 41 randomized controlled trials using sleep restriction intervention. The outcomes included: subjective hunger, appetite-regulating hormones, changes in brain activity, energy intake and expenditure, weight change, insulin sensitivity or resistance. Sleep restriction resulted in a significant increase in subjective hunger on a 100 mm scale (mean difference = 13.4, p < 0.001). Participants consumed 252.8 more kcal/d (p = 0.011) under sleep restriction than under normal sleep. Partial sleep restriction resulted in a 0.34 kg weight gain (p = 0.003). Sleep restriction also decreased insulin sensitivity (standardized mean difference = -0.70, p < 0.01). Significant changes in brain activity in response to food stimuli were observed under sleep restriction, particularly regions related to cognitive control and reward. Overall, we did not find strong evidence supporting the significant impact of sleep restriction on mean leptin or ghrelin levels or energy expenditure. Findings from this review enhanced our knowledge about the detrimental effects of sleep restriction on metabolism and provided novel directions in preventing metabolic diseases including obesity and diabetes.

8.
Gene ; 687: 156-165, 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30458287

RESUMO

MicroRNAs (miRNAs), small noncoding RNA molecules, have emerged as important factors during intervertebral disc degeneration. This study was to determine whether miR-202-3p regulates interleukin-1ß (IL-1ß)-induced expression of matrix metalloproteinase 1 (MMP-1) in human nucleus pulposus (NP) cells. Human NP cells were stimulated with IL-1ß in vitro. MicroRNA arrays were used to determine the expression profile of 1971 human miRNAs and the miRNAs targets were identified using bioinformatics. In IL-1ß-stimulated NP cells, 10 microRNAs were down-regulated, 2 microRNAs were up-regulated. There was a significant reduction in hsa-miR-202-3p (miR-202-3p) expression in the severe degenerative disc compared with mild degenerative disc. Down-regulation of miR-202-3p expression by IL-1ß was correlated with up-regulation of MMP-1 expression in human NP cells. IL-1ß-induced activation of MAP kinase (MAPK) and nuclear factor-κB (NF-κB) decreased miR-202-3p expression and induced MMP-1 expression. MiR-202-3p suppressed IL-1ß-induced MMP-1 production. Conversely, treatment with anti-miR-202-3p remarkably increased MMP-1 production. In addition, mutation of the miR-202-3p binding site in the 3'-UTR of MMP-1 mRNA abolished miR-202-3p-mediated repression of reporter activity. Functional analysis showed that miR-202-3p could decrease type II collagen degradation, whereas overexpression of MMP-1 by Lentiviral-shMMP-1 abolished the effect of miR-202-3p on type II collagen degradation. These results suggest that miR-202-3p is an important regulator of MMP-1 in human nucleus pulposus and may contribute to the development of intervertebral disc degeneration.

9.
Cell Physiol Biochem ; 49(6): 2463-2482, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30261504

RESUMO

BACKGROUND/AIMS: Intervertebral discs consist of an extracellular matrix (ECM) with a central gelatinous nucleus pulposus (NP) enclosed in an outer layer known as the annulus fibrosus. ECM metabolic disorders result in loss of boundary between the annulus fibrosus and NP, which can lead to intervertebral disc degeneration (IDD). Proinflammatory cytokines, such as interleukin (IL)-1ß, mediate the progression of IDD. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD) and is known to be induced by IL-1ß. APO866 is an inhibitor of NAD biosynthesis and is involved in autophagy. LC3 (microtubule-associated protein 1 light chain 3) is a key regulator of autophagy and is used as an indicator of increased autophagy. Herein, we investigate the role of APO866 in regulating autophagy in NP cells and IL-1ß mediated NP cell degeneration and apoptosis. METHODS: NP cells were extracted from IDD tissues and cultured in DMEM/F12 medium. Nampt was induced by different concentrations of IL-1ß (0, 0.5, 1, 5, 10 ng/mL) for 24 h or NP cells were treated with 10 ng/mL IL-1ß for 0, 6, 12, 48 h. QRT-PCR and western blots were used to detect Nampt and ECM-related protein expression in NP tissue of patients with IDD and in NP cells. Confocal analysis was used to detect membrane-bound LC3, Aggrecan, and Collagen II. RESULTS: Nampt is expressed in NP tissue at higher levels in severe grades of IDD (Grade IV and V) compared with low grades (Grade II and III). In NP cells, 10 ng/mL IL-1ß induced Nampt expression for 48 h, increased expression of the degradative-associated proteins, ADAMTS4/5 and MMP-3/13, and decreased expression of ECM-related proteins, Aggrecan and Collagen II. However, the Nampt inhibitor APO866 blocked IL-1ß induction, and the knockdown of Nampt expression increased the expression of ECM proteins that were inhibited by IL-1ß. Moreover, evidence provided by the autophagic markers LC3 and Beclin-1 indicated that APO866 induced NP cell autophagy. Furthermore, although APO866 inhibited the downregulated expression of ECM-related proteins by IL-1ß, this function was blocked by autophagy inhibitor, 3-methyladenine. CONCLUSION: APO866 protects NP cells and induces autophagy by inhibiting IL-1ß-induced NP cell degeneration and apoptosis, which may have therapeutic potential in IDD.


Assuntos
Acrilamidas/farmacologia , Autofagia/efeitos dos fármacos , Interleucina-1beta/farmacologia , Degeneração do Disco Intervertebral/patologia , Nicotinamida Fosforribosiltransferase/metabolismo , Piperidinas/farmacologia , Proteína ADAMTS4/metabolismo , Agrecanas/metabolismo , Células Cultivadas , Colágeno Tipo II/metabolismo , Citocinas/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Degeneração do Disco Intervertebral/metabolismo , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Núcleo Pulposo/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo
10.
Bone ; 117: 161-170, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30236554

RESUMO

Tumor Necrosis Factor-α (TNF-α)-inhibited osteogenic differentiation of mesenchymal stem cells (MSCs) contributes to impaired bone formation, which plays a central role in the pathogenesis of postmenopausal osteoporosis. However, the exact mechanisms of TNF-α-inhibited osteoblast differentiation have not been fully elucidated. Multiple P2 purinoceptor subtypes are expressed in several species of osteoblasts and are confirmed to regulate bone metabolism. The purpose of this study is to investigate whether P2 purinoceptors are involved in TNF-α-inhibited osteoblast differentiation. This study shows TNF-α increased P2Y2 receptor expression in the differentiation of MSCs into osteoblasts in a noticeable manner. Overexpressing or silencing of the P2Y2 receptor either impaired or promoted osteogenic differentiation of MSCs significantly. Silencing of the P2Y2 receptor attenuated the inhibitory effects of TNF-α on osteoblastic differentiation of MSCs. In addition, silencing of the P2Y2 receptor evidently alleviated TNF-α-inhibited MSC proliferation. P2Y2 receptor expression was mechanistically upregulated by TNF-α mainly through extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. Overall, our results revealed a novel function of the P2Y2 receptor and suggested suppressing the P2Y2 receptor may be an effective strategy to promote bone formation in estrogen deficiency-induced osteoporosis.

11.
J Cell Physiol ; 233(10): 6589-6602, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29150945

RESUMO

Discogenic low back pain (DLBP) is extremely common and costly. Effective treatments are lacking due to DLBP's unknown pathogenesis. Currently, there are no in vivo mouse models of DLBP, which restricts research in this field. The aim of this study was to establish a reliable DLBP model in mouse that captures the pathological changes in the disc and allows longitudinal pain testing. The model was generated by puncturing the mouse lumbar discs (L4/5, L5/6, and L6/S1) and removing the nucleus pulposus using a microscalpel under the microscope. Histology, molecular pathways, and pain-related behaviors were examined. Over 12 weeks post-surgery, animals displayed the mechanical, heat, and cold hyperalgesia along with decreased burrowing and rearing. Histology showed progressive disc degeneration with loss of disc height, nucleus pulposus reduction, proteoglycan depletion, and annular fibrotic disorganization. Immunohistochemistry revealed a substantial increase in inflammatory mediators at 2 and 4 weeks. Nerve growth factor was upregulated from 2 weeks to the end of the experiment. Nerve fiber ingrowth was induced in the injured discs after 4 weeks. Disc-puncture also produced an upregulation of neuropeptides in dorsal root ganglia neurons and an activation of glial cells in the spinal cord dorsal horn. These findings indicate that the cellular and structural changes in discs, as well as peripheral and central nervous system plasticity, paralleled persistent, and robust behavioral pain responses. Therefore, this mouse DLBP model could be used to investigate mechanisms underlying discogenic pain, thereby facilitating effective drug screening and development of treatments for DLBP.

12.
Sleep Breath ; 22(2): 287-295, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28812180

RESUMO

Obstructive sleep apnea (OSA) has many serious consequences, and one of these may be the exacerbation of type 2 diabetes mellitus (T2DM). Reports on the effect of continuous positive airway pressure (CPAP) on glucose metabolism in people with T2DM and OSA are conflicting. Therefore, the purpose of this review was to examine the effect of CPAP treatment on glucose metabolism by synthesizing findings from randomized controlled trials. The PRISMA review protocol was developed and registered in PROSPERO. A systematic search of PubMed, CINAHL, Embase, Web of Science, PsycInfo, and Cochrane was conducted from inception to March 2017. The Cochrane risk of bias tool was used to assess the study quality. Review Manager (v5.2) was used for the meta-analyses, and the standardized mean difference was calculated. Six studies consisting of 496 participants were included in this review. The meta-analyses indicated that CPAP treatment did not have significant impact on glucose metabolism measured by A1C (mean difference = 0.05, 95% CI - 0.14 to 0.24, P = 0.61), fasting insulin level (mean difference = - 2.34, 95% CI - 8.19 to 3.51, P = 0.43), and fasting glucose (mean difference = - 0.05, 95% CI - 0.52 to 0.42, P = 0.84). As expected, CPAP treatment can improve daytime sleepiness (mean difference = - 2.68, 95% CI - 3.91 to - 1.54, P < 0.001). Findings of this meta-analysis do not substantiate a positive effect of CPAP on glucose metabolism in people with T2DM and coexisting OSA. Future large-scale clinical trials with a longer treatment duration and better CPAP compliance are warranted.

13.
J Orthop Res ; 36(5): 1305-1312, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28921656

RESUMO

Chronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain (LBP). This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of LBP can be divided into the following five categories: Discogenic LBP, radicular back pain, facet joint osteoarthritis back pain, muscle-induced LBP, and spontaneous occurring LBP models. These models are important not only for enhancing our knowledge of how LBP is generated, but also for the development of novel therapeutic regimens to treat LBP in patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1305-1312, 2018.

14.
J Cell Biochem ; 119(1): 566-579, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28608941

RESUMO

The enzyme chondroitin polymerizing factor (ChPF) is primarily involved in extension of the chondroitin sulfate backbone required for the synthesis of sulfated glycosaminoglycan (sGAG). Transforming growth factor beta (TGF-ß) upregulates sGAG synthesis in nucleus pulposus cells; however, the mechanisms mediating this induction are incompletely understood. Our study demonstrated that ChPF expression was negatively correlated with the grade of degenerative intervertebral disc disease. Treatment of nucleus pulposus cells with TGF-ß induced ChPF expression and enhanced Smad2/3, RhoA/ROCK activation, and the JNK, p38, and ERK1/2 MAPK signaling pathways. Selective inhibitors of Smad2/3, RhoA or ROCK1/2, and knockdown of Smad3 and ROCK1 attenuated ChPF expression and sGAG synthesis induced by TGF-ß. In addition, we showed that RhoA/ROCK1 signaling upregulated ChPF via activation of the JNK pathway but not the p38 and ERK1/2 signaling pathways. Moreover, inhibitors of JNK, p38 and ERK1/2 activity also blocked ChPF expression and sGAG synthesis induced by TGF-ß in a Smad3-independent manner. Collectively, our data suggest that TGF-ß stimulated the expression of ChPF and sGAG synthesis in nucleus pulposus cells through Smad3, RhoA/ROCK1 and the three MAPK signaling pathways. J. Cell. Biochem. 119: 566-579, 2018. © 2017 Wiley Periodicals, Inc.


Assuntos
Disco Intervertebral/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , N-Acetilgalactosaminiltransferases/biossíntese , Proteína Smad3/biossíntese , Fator de Crescimento Transformador beta/farmacologia , Quinases Associadas a rho/biossíntese , Proteína rhoA de Ligação ao GTP/biossíntese , Adolescente , Adulto , Idoso , Feminino , Glicosaminoglicanos/biossíntese , Humanos , Masculino , Pessoa de Meia-Idade
15.
Oncotarget ; 8(30): 49303-49317, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28514734

RESUMO

Intervertebral disc degeneration (IDD) is characterized by dehydration and loss of extracellular matrixes in the nucleus pulposus region. Chondroitin sulfate has been found to be the water-binding molecule that played a key role in IDD. Although investigators have reported that inflammatory cytokines are involved in the reduction of chondroitin sulfate in IDD, but the underlying mechanism is unrevealed. Since chondroitin sulfate synthesis is controlled by chondroitin sulfate glycosyltransferases CHSY-1/2/3 and CSGALNACT-1/2, their functional role and regulatory mechanism in IDD is not fully studied. Here, we set out to investigate the function and regulatory roles of these factors during IDD development. We found that among these chondroitin sulfate glycosyltransferases, CHSY-1/2/3 are significantly down-regulated in severe IDD samples than mild IDD samples. In vitro experiments revealed that Interleukin-1ß and Tumor Necrosis Factor-α stimulation led to significant reduction of CHSY-1/2/3 at protein level than mRNA level in NP cells, indicating a post-transcriptional regulatory mechanisms are involved. By computational prediction and analysis, we found that inflammatory cytokines stimulated microRNA-194 and -515 target CHSY-1/2/3 mRNA and significantly interrupt their translation and downstream chondroitin sulfate deposition. Inhibition of microRNA-194 and -515 however, significantly rescued CHSY-1/2/3 expressions and chondroitin sulfate deposition. These findings together demonstrated a vital role of inflammatory stimulated microRNAs in promoting intervertebral disc degeneration by interrupt chondroitin sulfate synthesis, which may provide new insights into the mechanism and therapeutic approaches in IDD.


Assuntos
Sulfatos de Condroitina/biossíntese , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , MicroRNAs/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Biomarcadores , Vias Biossintéticas , Biologia Computacional/métodos , Citocinas/metabolismo , Imunofluorescência , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/diagnóstico , Pessoa de Meia-Idade , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Interferência de RNA , RNA Mensageiro/genética , Índice de Gravidade de Doença
16.
Am J Transl Res ; 9(1): 79-89, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28123635

RESUMO

We previously showed that bone mesenchymal stem cells (BMSCs) inhibit interleukin-1 beta (IL-1ß) induced degenerative effects in NP cells by their paracrine activity, but the anti-inflammatory and anti-apoptotic effect of BMSC paracrine activity and the relative signaling pathway were not further investigated in annulus fibrosus (AF) cells. In this study, AF cells were exposed to IL-1ß, which was applied to mimic intervertebral disc degeneration (IDD) in vitro. Indirect co-culture with BMSCs in a transwell co-culture system reduced the activity of nuclear factor-κB-p65 (NF-κB-p65) through the restoration of its inhibitor IκBa. Real time polymerase chain reaction (PT-PCR) and Western blotting revealed that the up-regulation of MMP-3 and MMP-13 induced by IL-1ß were impeded by BMSC co-culture, and the decrease in aggrecan, collagen I and TIMP-1 were reversed. An ELISA showed that the increased inflammatory factors, such as nitrite, prostaglandin E-2 (PGE-2), IL-6 and cyclooxygenase-2 (COX-2), were decreased by the BMSC co-culture. Furthermore, the apoptosis rate of AF cells were detected by flow cytometry, and the apoptosis-related proteins, such as Bax, Bcl-2 and caspase-3, were analyzed by Western blotting and ELISA. The changes in mitochondrial membrane potentials were also detected by confocal microscopy. The results showed that IL-1ß induced apoptosis of AF cells was attenuated by co-culturing, which suppressed the functions of the mitochondria function. We suggest that BMSC paracrine activity has an anti-inflammation effect and anti-apoptotic effect on IDD, and it is mediated, at least in part, via the relative NF-κF and mitochondrial apoptotic pathways in AF cells.

18.
Sci Rep ; 6: 21580, 2016 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-26868491

RESUMO

Ossification of the posterior longitudinal ligament (OPLL) is a genetic disorder which involves pathological heterotopic ossification of the spinal ligaments. Although studies have identified several genes that correlated with OPLL, the underlying regulation network is far from clear. Through small RNA sequencing, we compared the microRNA expressions of primary posterior longitudinal ligament cells form OPLL patients with normal patients (PLL) and identified 218 dysregulated miRNAs (FDR < 0.01). Furthermore, assessing the miRNA profiling data of multiple cell types, we found these dysregulated miRNAs were mostly OPLL specific. In order to decipher the regulation network of these OPLL specific miRNAs, we integrated mRNA expression profiling data with miRNA sequencing data. Through computational approaches, we showed the pivotal roles of these OPLL specific miRNAs in heterotopic ossification of longitudinal ligament by discovering highly correlated miRNA/mRNA pairs that associated with skeletal system development, collagen fibril organization, and extracellular matrix organization. The results of which provide strong evidence that the miRNA regulatory networks we established may indeed play vital roles in OPLL onset and progression. To date, this is the first systematic analysis of the micronome in OPLL, and thus may provide valuable resources in finding novel treatment and diagnostic targets of OPLL.


Assuntos
Regulação da Expressão Gênica , Ligamentos Longitudinais/metabolismo , MicroRNAs/biossíntese , Ossificação do Ligamento Longitudinal Posterior/metabolismo , Células Cultivadas , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ligamentos Longitudinais/patologia , Masculino , Ossificação do Ligamento Longitudinal Posterior/diagnóstico , Ossificação do Ligamento Longitudinal Posterior/patologia
19.
Sci Rep ; 6: 21190, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26877238

RESUMO

Intervertebral disc degeneration (IDD) is characterized by disordered extracellular matrix (ECM) metabolism, implicating subdued anabolism and enhanced catabolic activities in the nucleus pulposus (NP) of discs. Pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) are considered to be potent mediators of ECM breakdown. Hemeoxygenase-1 (HO-1) has been reported to participate in cellular anti-inflammatory processes. The purpose of this study was to investigate HO-1 modulation of ECM metabolism in human NP cells under IL-1ß stimulation. Our results revealed that expression of HO-1 decreased considerably during IDD progression. Induction of HO-1 by cobalt protoporphyrin IX attenuated the inhibition of sulfate glycosaminoglycan and collagen type II (COL-II) synthesis and ameliorated the reduced expressions of aggrecan, COL-II, SOX-6 and SOX-9 mediated by IL-1ß. Induction of HO-1 also reversed the effect of IL-1ß on expression of the catabolic markers matrix metalloproteinases-1, 3, 9 and 13. This was combined with inhibition of the activation of mitogen-activated protein kinase signaling. These findings suggest that HO-1 might play a pivotal role in IDD, and that manipulating HO-1 expression might mitigate the impairment of ECM metabolism in NP, thus potentially offering a novel therapeutic approach to the treatment of IDD.


Assuntos
Matriz Extracelular/metabolismo , Heme Oxigenase-1/biossíntese , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Adulto , Idoso , Agrecanas/biossíntese , Agrecanas/genética , Células Cultivadas , Colágeno Tipo II/biossíntese , Colágeno Tipo II/genética , Matriz Extracelular/patologia , Feminino , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/administração & dosagem , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/tratamento farmacológico , Degeneração do Disco Intervertebral/fisiopatologia , Masculino , Metaloproteinases da Matriz/biossíntese , Pessoa de Meia-Idade , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Protoporfirinas/biossíntese
20.
J Bone Miner Res ; 31(5): 1003-14, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26679066

RESUMO

Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by brittle bones with increased fracture risk. Although current treatment options to improve bone strength in OI focus on antiresorptive bisphosphonates, controlled clinical trials suggest they have an equivocal effect on reducing fracture risk. Strontium ranelate (SrR) is a promising therapy with a dual mode of action that is capable of simultaneously maintaining bone formation and reducing bone resorption, and may be beneficial for the treatment of OI. In this study, SrR therapy was investigated to assess its effects on fracture frequency and bone mass and strength in an animal model of OI, the oim/oim mouse. Three-week-old oim/oim and wt/wt mice were treated with either SrR or vehicle (Veh) for 11 weeks. After treatment, the average number of fractures sustained by SrR-treated oim/oim mice was significantly reduced compared to Veh-treated oim/oim mice. Micro-computed tomographic (µCT) analyses of femurs showed that both trabecular and cortical bone mass were significantly improved with SrR treatment in both genotypes. SrR significantly inhibited bone resorption, whereas bone formation indices were maintained. Biomechanical testing revealed improved bone structural properties in both oim/oim and wild-type (wt/wt) mice under the treatment, whereas no significant effects on bone brittleness and material quality were observed. In conclusion, SrR was able to effectively reduce fractures in oim/oim mice by improving bone mass and strength and thus represents a potential therapy for the treatment of pediatric OI. © 2015 American Society for Bone and Mineral Research.


Assuntos
Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/prevenção & controle , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Tiofenos/farmacologia , Microtomografia por Raio-X , Animais , Modelos Animais de Doenças , Fraturas Ósseas/genética , Incidência , Camundongos , Camundongos Mutantes , Osteogênese Imperfeita/genética
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