Qianyu Zhuang

Glucocorticoid Receptor and Sequential P53 Activation by Dexamethasone Mediates Apoptosis and Cell Cycle Arrest of Osteoblastic MC3T3-E1 Cells

Glucocorticoids play a pivotal role in the proliferation of osteoblasts, but the underlying mechanism has not been successfully elucidated. In this report, we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3-E1 cells. It was found that the inhibitory effects were largely attributed to apoptosis and G1 phase arrest. Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor (GR), as they were abolished by GR blocker RU486 pre-treatment and GR interference. G1 phase arrest and apoptosis were accompanied with a p53-dependent up-regulation of p21 and pro-apoptotic genes NOXA and PUMA. We also proved that dexamethasone can’t induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference. These data demonstrate that proliferation of MC3T3-E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P53 activation.

Association study of tryptophan hydroxylase 1 and arylalkylamine N-acetyltransferase polymorphisms with adolescent idiopathic scoliosis in Han Chinese.

Study Design. A genetic association study of tryptophan hydroxylase 1 gene (TPH1) and arylalkylamine N-acetyltransferase gene(AANAT) with adolescent idiopathic scoliosis (AIS) in Han Chinese. Objective. To access whether TPH1 and AANAT polymorphisms are associated with the predisposition, gender, and/or severity of AIS. Summary of Background Data. Studies have shown that AIS is a multifactorial inheritance disease, but the etiology is still unknown. In addition, several lines of evidence show that melatonin deficiency is closely associated with AIS, although there are still doubts and debates. Some polymorphisms in TPH1 and AANAT, the genes of 2 critical enzymes involved in melatonin biosynthesis, may contribute to variability of melatonin production in pineal glands. Methods. We genotyped 16 reported single nuclear polymorphisms (SNPs) present in TPH1 and AANAT in 103 AIS patients and 108 controls with matched sex and age. The data of 6 SNPs with minor allele frequence (MAF) above 5% were analyzed by the allelic and genotypic association analysis, the genotype-phenotype (gender and Cobb angle) association analysis, and the haplotype analysis. Results. The single SNP analysis showed that rs10488682, located in the promoter region of TPH1, was related with the occurrence of AIS (P < 0.05). No SNP was found to be correlated with gender or Cobb angle. Two makers (rs8176799 and rs2108977) in TPH1 were found to be in strong LD [ D′ = 1.0 (95% CI, 0.9–1.0), γ2 = 0.501, LOD = 18.93] in the controls. Both global haplotype analysis and individual haplotype analysis showed that there was no haplotype significantly associated with AIS in this LD block. Conclusion. TPH1 polymorphisms were associated with AIS but not with gender and Cobb angle in AIS patients. AANAT polymorphisms were not associated with AIS. These results suggested that TPH1 was an AIS predisposition gene, and there was a close relationship between the dyssynthesis of melatonin and AIS.

Cemented versus uncemented hemiarthroplasty for femoral neck fractures in elderly patients: a meta-analysis.

Objective Controversy still exists regarding using cemented or uncemented hemiarthroplasty for femoral neck fractures in elderly patients. The aim of this study is to compare the effectiveness and safety of the two surgical techniques in femoral neck fracture patients over 70 years old. Methods We searched PUBMED, EMBASE, Cochrane Library, CNKI and VIP Database from inception to December 2012 for relevant randomized controlled trials (RCTs). Outcomes of interest include postoperative hip function, residue pain, complication rates, mortality, reoperation rate, operation time and intraoperative blood loss. Odds ratios (OR) and weighted mean differences (WMD) from each trial were pooled using random-effects model or fixed-effects model given on the heterogeneity of the included studies. Results 7 RCTs involving 1,125 patients (1,125 hips) were eligible for meta-analysis. Our results demonstrate that cemented hemiarthroplasty is associated with better postoperative hip function (OR = 0.48, 95% CI, 0.31–0.76; P = 0.002), lower residual pain (OR = 0.43, 95%CI, 0.29–0.64; P<0.0001), less implant-related complications (OR = 0.15, 95%CI, 0.09–0.26; P<0.00001) and longer operation time (WMD = 7.43 min, 95% CI, 5.37–9.49 min; P<0.00001). No significant difference was observed between the two groups in mortality, cardiovascular and cerebrovascular complications, local complications, general complications, reoperation rate and intraoperative blood loss. Conclusions Compared with uncemented hemiarthroplasty, the existing evidence indicates that cemented hemiarthroplasty can achieve better hip function, lower residual pain and less implant-related complications with no increased risk of mortality, cardiovascular and cerebrovascular complications, general complications, local complications and reoperation rate in treating elderly patients with femoral neck fractures.

How to make the best use of intraoperative motor evoked potential monitoring? Experience in 1162 consecutive spinal deformity surgical procedures.

Study Design. A retrospective study of 1162 consecutive patients who underwent spinal deformity surgical procedures at our spine center from January 2010 to December 2013. Objective. To develop and evaluate a protocol of intraoperative motor evoked potential (MEP) monitoring with the warning criteria we had established on the basis of our clinical experiences and the review of previous literature. Summary of Background Data. Though MEPs monitoring have become widely used in spinal deformity surgery, different alarm criteria and response protocol used in different studies compromised their comparability; Furthermore, high false-positive rate of MEP reported by previous studies has become an increasingly prominent problem that will limit its clinical use and development. Methods. The intraoperative monitoring data of 1162 consecutive patients who underwent spinal deformity surgical procedures at our spine center were retrospectively analyzed. Age, sex, diagnosis, preoperative neurological status, intraspinal anomalies, baseline MEP, and MEP change were collected. The protocol with the warning criteria we had established was used. The false-positive rate, false-negative rate, and positive predictive value were calculated. Results. Significant intraoperative changes were seen in the MEP data in 52 (4.4%) of all the cases. In 25 cases among which, significant MEP changes were synchronously and logically associated with high-risk surgical maneuver (pedicle screw insertion, osteotomy, correction, etc.). The false-positive rate of MEP monitoring was 0.26% (3/1140), whereas the sensitivity and specificity of MEP for detection of clinically significant intraoperative cord injury were 100% and 99.7%, respectively. The positive predictive value of a MEP alert in terms of a new postoperative neurological deficit was 83.3%. Conclusion. Our study indicates that the appropriate use of MEP monitoring based on our protocol is able to obtain satisfying sensitivity and specificity and thus provide important information for intraoperative decision making. Level of Evidence: 4

Patellar Denervation in Total Knee Arthroplasty Without Patellar Resurfacing and Postoperative Anterior Knee Pain: A Meta-Analysis of Randomized Controlled Trials

The aim of this meta-analysis was to investigate whether patellar denervation with electrocautery (PD) after total knee arthroplasty (TKA) could reduce the postoperative anterior knee pain (AKP). Five randomized controlled trials (RCTs) with 572 patients and 657 knees were eligible for this meta-analysis. Our results showed that PD was associated with less AKP, lower visual analogue scale (VAS), higher patellar scores and better knee function compared with no patellar denervation (NPD). Complications did not differ significantly between the two groups. The existing evidence indicates that PD may be a better approach, as it improves both anterior knee pain and knee function after TKA. Future multi-center randomized controlled studies with large sample sizes are required to verify the current findings.

Differential proteome analysis of bone marrow mesenchymal stem cells from adolescent idiopathic scoliosis patients.

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. The cause and pathogenesis of scoliosis and the accompanying generalized osteopenia remain unclear despite decades of extensive research. In this study, we utilized two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) to analyze the differential proteome of bone marrow mesenchymal stem cells (BM-MSCs) from AIS patients. In total, 41 significantly altered protein spots were detected, of which 34 spots were identified by MALDI-TOF/TOF analysis and found to represent 25 distinct gene products. Among these proteins, five related to bone growth and development, including pyruvate kinase M2, annexin A2, heat shock 27 kDa protein, γ-actin, and β-actin, were found to be dysregulated and therefore selected for further validation by Western blot analysis. At the protein level, our results supported the previous hypothesis that decreased osteogenic differentiation ability of MSCs is one of the mechanisms leading to osteopenia in AIS. In summary, we analyzed the differential BM-MSCs proteome of AIS patients for the first time, which may help to elucidate the underlying molecular mechanisms of bone loss in AIS and also increase understanding of the etiology and pathogenesis of AIS.

Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post-total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel-group trial

Introduction Total knee arthroplasty (TKA) has been regarded as a most painful orthopaedic surgery. Although many surgeons sequentially use parecoxib and celecoxib as a routine strategy for postoperative pain control after TKA, high quality evidence is still lacking to prove the effect of this sequential regimen, especially at the medium-term follow-up. The purpose of this study, therefore, is to evaluate efficacy and safety of postoperative intravenous parecoxib sodium followed by oral celecoxib in patients with osteoarthritis (OA) undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of parecoxib and celecoxib can achieve less morphine consumption over the postoperative 2 weeks, as well as better pain control, quicker functional recovery in the postoperative 6 weeks and less opioid-related adverse events during the 12-week recovery phase. Methods and analysis This study is designed as a multicentre, randomised, double-blind, parallel-group and placebo-controlled trial. The target sample size is 246. All participants who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either the parecoxib/celecoxib group or placebo group. The randomisation and allocation will be study site based. The study will consist of three phases: an initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points consist of the postoperative visual analogue scale score, knee joint function, quality of life, local skin temperature, erythrocyte sedimentation rate, C reactive protein, cytokines and blood coagulation parameters. Safety end points will be monitored too. Ethics and dissemination Ethics approval for this study has been obtained from the Ethics Committee, Peking Union Medical College Hospital, China (Protocol number: S-572) Study results will be available as published manuscripts and presentations at national and international meetings. Trial registration number NCT02198924.

Total hip/knee arthroplasty in the treatment of tumor-induced osteomalacia patients: More than 1 year follow-up

Background Tumor-induced osteomalacia (TIO) may result in a better prognosis after complete resection of the causative neoplasm. However, tumors located proximal to the articular surface of the metaphysis remain largely uninvestigated. Methods A retrospective study of sixteen patients was undertaken to evaluate treatment of tumors with joint arthroplasty and tumor resection. The bone metabolism index, hip/knee joint function, arthroplasty complications and symptoms were followed up for at least 12 months in each patient. Results All patients presented with neoplasms situated in the articular surface of the metaphysis, with 13 cases undergoing hip arthroplasty and 3 undergoing knee arthroplasty. Treatment of the tumors with joint arthroplasty and tumor resection significantly and rapidly ameliorate bone metabolism indexes in patients with TIO (p<0.01), with no identified tumor recurrence. The joint function evaluation score was improved in 15 patients (93.75%). Complications in these patients included post-operative pain, joint squeaking and secondary hyperparathyroidism. Conclusions Joint arthroplasty that includes tumor-expanding resection appears to be a safe and appropriate method for the treatment of TIO patients with a neoplasm located in the metaphysis proximal to the articular surface. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Identification of Differential Genes Expression Profiles and Pathways of Bone Marrow Mesenchymal Stem Cells of Adolescent Idiopathic Scoliosis Patients by Microarray and Integrated Gene Network Analysis.

Study Design. Microarray approach and integrated gene network analysis. Objective. To explore the differential genetic expression profile, gene ontology terms, and Kyoto Encyclopedia of Genes and Genomes pathways in bone marrow mesenchymal stem cells (BM-MSCs) of idiopathic scoliosis (AIS) and non-AIS controls. Summary of Background Data. The pathogenesis of adolescent AIS and the accompanying generalized osteopenia remain unclear. Our previous study suggested increased proliferation ability and decreased osteogenic differentiation ability of BM-MSCs of AIS. Therefore, we hypothesized that MSCs may play a significant role in the etiology and pathogenesis of AIS. Methods. In this study, microarray analysis was used to identify differentially expressed genes (DEGs) of BM-MSCs from AIS patients compared with those from healthy individuals. Comprehensive bioinformatics analyses were then used to enrich datasets for gene ontology and pathway. Based on the gene signal transduction network analysis of DEGs contained in significant pathways, 24 potential crucial genes were selected for validation by reverse transcription polymerase chain reaction. Results. There are 1027 previously unrecognized DEGs in BM-MSCs from AIS patients. Pathway analysis revealed dysregulated mitogen-activated protein kinase (MAPK) signaling pathway, PI3K-Akt signaling pathway, calcium signaling pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway, ubiquitin-mediated proteolysis, and Notch signaling pathway, all of which have been reported to play an important role in regulating the osteogenic or adipogenic differentiation of MSCs. Furthermore, gene signal transduction networks analysis indicated that mitogen-activated protein kinase kinase 1 (MAP2K1), SMAD family member 3 (SMAD3), homeobox C6 (HOXC6), heat shock 70kDa protein 6 (HSPA6), general transcription factor IIi (GTF2I), CREB binding protein (CREBBP), phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2), and dual specificity phosphatase 2 (DUSP2) may play essential roles in AIS pathogenesis and accompanied osteopenia. Conclusion. This study reports the differential genes expression profiles of BM-MSCs from AIS patients and related potential pathways for the first time. These previously unrecognized genes and molecular pathways might play a significant role in not only the causal mechanism of osteopenia in AIS, but also the AIS initiation and development. The identification of these candidate genes provides novel insight into the underlying etiological mechanisms of AIS. Level of Evidence: N/A