CD34+ synovial fibroblasts exhibit high osteogenic potential in synovial chondromatosis.

Synovial chondromatosis (SC) is a disorder of the synovium characterized by the formation of osteochondral nodules within the synovium. This study aimed to identify the abnormally differentiated progenitor cells and possible pathogenic signaling pathways. Loose bodies and synovium were obtained from patients with SC during knee arthroplasty. Single-cell RNA sequencing was used to identify cell subsets and their gene signatures in SC synovium. Cells derived from osteoarthritis (OA) synovium were used as controls. Multi-differentiation and colony-forming assays were used to identify progenitor cells. The roles of transcription factors and signaling pathways were investigated through computational analysis and experimental verification. We identified an increased proportion of CD34+ sublining fibroblasts in SC synovium. CD34+CD31- cells and CD34-CD31- cells were sorted from SC synovium. Compared with CD34- cells, CD34+ cells had larger alkaline phosphatase (ALP)-stained area and calcified area after osteogenic induction. In addition, CD34+ cells exhibited a stronger tube formation ability than CD34- cells. Our bioinformatic analysis suggested the expression of TWIST1, a negative regulator of osteogenesis, in CD34- sublining fibroblasts and was regulated by the TGF-ß signaling pathway. The experiment showed that CD34+ cells acquired the TWIST1 expression during culture and the combination of TGF-ß1 and harmine, an inhibitor of Twist1, could further stimulate the osteogenesis of CD34+ cells. Overall, CD34+ synovial fibroblasts in SC synovium have multiple differentiation potentials, especially osteogenic differentiation potential, and might be responsible for the pathogenesis of SC.

Mechanically stimulated osteocytes maintain tumor dormancy in bone metastasis of non-small cell lung cancer by releasing small extracellular vesicles.

Although preclinical and clinical studies have shown that exercise can inhibit bone metastasis progression, the mechanism remains poorly understood. Here, we found that non-small cell lung cancer (NSCLC) cells adjacent to bone tissue had a much lower proliferative capacity than the surrounding tumor cells in patients and mice. Subsequently, it was demonstrated that osteocytes, sensing mechanical stimulation generated by exercise, inhibit NSCLC cell proliferation and sustain the dormancy thereof by releasing small extracellular vesicles with tumor suppressor micro-RNAs, such as miR-99b-3p. Furthermore, we evaluated the effects of mechanical loading and treadmill exercise on the bone metastasis progression of NSCLC in mice. As expected, mechanical loading of the tibia inhibited the bone metastasis progression of NSCLC. Notably, bone metastasis progression of NSCLC was inhibited by moderate exercise, and combinations with zoledronic acid had additive effects. Moreover, exercise preconditioning effectively suppressed bone metastasis progression. This study significantly advances the understanding of the mechanism underlying exercise-afforded protection against bone metastasis progression.

Follow-up study of isolated calf muscular vein thrombosis for anticoagulant therapy after primary hip and knee arthroplasty.

BACKGROUND: Although isolated calf muscular vein thrombosis (ICMVT) is commonly seen after hip and knee arthroplasty, no treatment guidelines for ICMVT after joint replacement are available. The purpose of this study was to evaluate the outcomes of patients with ICMVT for anticoagulant therapy at different time points after primary hip and knee arthroplasty. METHODS: Patients with ICMVT after primary hip and knee arthroplasty were included in the study. Diagnosis was established with Doppler ultrasound. Patients were followed up clinically and with Doppler ultrasound at 1, 2, and 3 months. The outcomes were efficacy (complete resolution) and acceptability (hemorrhagic events). Anticoagulant therapy at curative dosage was prescribed for 1 month and was extended for 2 additional months in case of incomplete resolution at 1 month or if propagation was present. The chi-square test was used to compare the outcomes at different time points. RESULTS: 302 patients were taken hip and knee arthroplasty from January 2021 to May 2022, in which 51 patients presented with 51 ICMVTs postoperatively. The incidence of ICMVT was about 16.89%. Resolution of ICMVT was considered complete at 1, 2, and 3 months at 36.73%, 61.22%, and 91.84%, respectively, with significant differences among the time points (P < 0.05). All patients with ICMVT receiving anticoagulant therapy remained free of propagations and hemorrhagic events within 3 months. CONCLUSION: Our findings provide new insights into the anticoagulant therapy for ICMVT after primary hip and knee arthroplasty, taking oral Rivaroxaban for 3 months is effective and safe, which contributes to provide the reference for clinical practice.

Comparative Efficacy and Safety of Measures for the Treatment of Adults with Isolated Calf Muscular Vein Thrombosis: A Systematic Review and Network Meta-analysis.

BACKGROUND: Isolated calf muscular vein thrombosis (ICMVT) can result in pulmonary embolism, but the treatment of ICMVT remains controversial. Therefore, the purpose of the present study was to investigate the optimal treatment for the ICMVT by comparing the efficacy and safety of different treatments. METHODS: A network meta-analysis was conducted to search for studies published from database inception to April 30, 2022, that compared the outcomes of 2 or more treatments for ICMVT. The primary outcomes were efficacy (resolution rate) and safety (adverse reactions). Data were extracted following predefined hierarchy and the Cochrane Collaboration risk of bias tool was used to evaluate the methodological quality of the included studies. We estimated summary odds ratios with 95% credibility intervals using Bayesian network meta-analysis with random effects. RESULTS: A total of 16 studies were enrolled in the study. In terms of efficacy and safety, urokinase thrombolysis combined with low-molecular-weight heparin (LMWH) was most effective but had the lowest safety, while physical therapy was safest but had the lowest efficacy. More important, direct oral factor Xa inhibitors were most likely to be second most effective and safe compared with other treatments. For the duration of treatment, anticoagulant therapy for at least 3 months could effectively increase the resolution rate of ICMVT. CONCLUSIONS: Considering both efficacy and safety, taking direct oral factor Xa inhibitors for at least 3 months was the optimal treatment compared to LMWH, urokinase thrombolysis combined LMWH, physical therapy and warfarin for patients with ICMVT.

A prediction nomogram for deep venous thrombosis risk in patients undergoing primary total hip and knee arthroplasty: a retrospective study.

INTRODUCTION: Deep venous thrombosis (DVT) prediction after total hip and knee arthroplasty remains challenging. Early diagnosis and treatment of DVT are crucial. This research aimed to develop a nomogram for early DVT prediction. METHODS: A total of 317 patients undergoing primary total hip and knee arthroplasty in Sun Yat-sen Memorial Hospital were enrolled between May 2020 and September 2022. Data from May 2020 to February 2022 were used as the development datasets to build the nomogram model (n = 238). Using multivariate logistic regression, independent variables and a nomogram for predicting the occurrence of DVT were identified. Datasets used to validate the model for internal validation ranged from March 2022 to September 2022 (n = 79). The nomogram's capacity for prediction was also compared with the Caprini score. RESULTS: For both the development and validation datasets, DVT was found in a total of 38 (15.97%) and 9 patients (11.39%) on post-operative day 7 (pod7), respectively. 59.6% patients were symptomatic DVT (leg swelling). The multivariate analysis revealed that surgical site (Knee vs. Hip), leg swelling and thrombin-antithrombin complex (TAT) were associated with DVT. The previously indicated variables were used to build the nomogram, and for the development and validation datasets, respectively. In development and validation datasets, the area under the receiver operating characteristic curve was 0.836 and 0.957, respectively. In both datasets, the predictive value of the Nomogram is greater than the Caprini score. CONCLUSIONS: A proposed nomogram incorporating surgical site (Knee vs. Hip), leg swelling, and thrombin antithrombin complex (TAT) may facilitate the identification of patients who are more prone to develop DVT on pod7.

Reliability and validity of the functional combined anteversion measurement method using standing lateral radiography after total hip arthroplasty.

Background: The functional safe zone of combined anteversion (CA) shows a superior predictive value for dislocation after total hip arthroplasty (THA) compared to that of the Lewinnek safe zone. Thus, it is necessary to establish a feasible and accurate method for assessing CA for the evaluation of dislocation risk. We aimed to evaluate the reliability and validity of using standing lateral (SL) radiographs for determining CA. Methods: Sixty-seven patients who underwent SL radiography and computed tomography (CT) scans after THA were included. Radiographic CA values were obtained via the calculation of the sum of the acetabular cup and femoral stem anteversion (FSA) measurements as obtained from the SL radiographs. Acetabular cup anteversion (AA) was measured based on the tangential line to the face of the cup, whereas FSA was calculated using the developed formula based on the neck-shaft angle. The intra-observer and inter-observer reliabilities for each measurement were examined. Radiological CA values were compared with the CT scan measurements to evaluate their validity. Results: The intra-observer and inter-observer agreements of the SL radiography were excellent [intraclass correlation coefficient (ICC) ≥0.90]. The radiographic measurements correlated well with the CT scan measurements (r=0.869, P<0.001). The mean difference between the radiographic and CT scan measurements was -0.55°±4.68° and ranged from 0.3° to 2.2° in terms of the 95% confidence interval (CI). Conclusions: SL radiography is a reliable and valid imaging tool for the assessment of functional CA.

A Single-Cell RNA-Sequencing Analysis of Distinct Subsets of Synovial Macrophages in Rheumatoid Arthritis.

The polarization states and molecular signatures of macrophages in the synovium of patients with rheumatoid arthritis (RA) are not well understood. We aimed to identify specific subpopulations of macrophages and their features in RA synovium thereby providing a theoretical basis for treatment of RA. Single-cell RNA sequencing (scRNA-seq) was used to identify cell subsets and their gene signatures in synovial cells of patients with RA and osteoarthritis (OA). Spatial distribution of macrophages was visualized by deconvolving spatial transcriptomic data with scRNA-seq data. Flow cytometry and immunofluorescence were applied to investigate the expression of macrophage polarization indicators CD86 and CD206. Trajectory analysis was used to determine differentiation relationships. Transcription factor (TF) analysis was performed to find specific TFs. scRNA-seq identified three cell clusters of macrophages: M0-like MARCO+ Mϕ1, M2-like CSF1R+ Mϕ2, and M1-like PLAUR+ Mϕ3. Mϕ1 distributed widely in the synovium, whereas Mϕ2 and Mϕ3 distributed sparsely. CD86 and CD206 were both upregulated in macrophages of RA synovium, especially in lining layer. Trajectory analysis showed that Mϕ1 existed at the start of the differentiation trajectory. HOXB6, STAT1, and NFKB2 were TFs specific to Mϕ1, Mϕ2, and Mϕ3 under RA condition, respectively. Compared with in OA condition, three macrophage clusters upregulated CXCL2, CXCL1, IL1B, TNFAIP3, ICAM1, CXCL3, PLAU, CCL4L2, CCL4, and TNF in NF-kappa B signaling pathway. The identification of macrophage subsets with different polarized states and their molecular signatures provided a more precise understanding of macrophages, which may contribute to the development of novel therapeutic strategy for RA.

Post-operative complications of total knee arthroplasty in patients with hypertension.

BACKGROUND: Hypertension is one of the most common comorbidities among patients undergoing surgery. However, few studies have focused on patients undergoing knee arthroplasty, and most of them had small sample sizes. This study aimed to analyze post-operative complications associated with hypertension in patients who underwent knee replacement surgery. METHODS: Data from the 2019 National Inpatient Sample (NIS) database were used. Patients who underwent primary total knee arthroplasty (pTKA) and those who underwent aseptic revision total knee arthroplasty (rTKA) were analyzed separately. Propensity score matching was performed to reduce the effects of demographic factors and comorbidities other than hypertension on post-operative complications. A multinomial logistic regression that included all significantly different demographics and comorbidities was performed to verify the results and evaluate the odds ratios. RESULTS: A total of 107,981 patients who underwent pTKA and 6571 who underwent rTKA owing to mechanical complications were identified in the 2019 NIS database. Compared with the non-hypertension group, patients with hypertension had a higher risk of developing acute renal failure and electrolyte disorders after TKA. Further analysis revealed that hyponatraemia and hypokalaemia were associated with hypertension. CONCLUSIONS: Hypertension was associated with the incidence of acute renal failure after TKA. It is important to identify patients with risk factors for acute renal failure (in addition to hypertension) and take careful measures to prevent acute renal failure in them.

Thrombin antithrombin complex concentration as an early predictor of deep vein thrombosis after total hip arthroplasty and total knee arthroplasty.

AIM: Early predictive markers of venous thromboembolism (VTE) after total hip arthroplasty (THA)/total knee arthroplasty (TKA) remain unclear. Our study identified early predictive markers for VTE after THA/TKA. METHODS: A single-institution retrospective review study was conducted between May 2020 and April 2022 (n = 256). All patients underwent Doppler ultrasounds exam in preoperation and seventh day after surgery. Deep vein thrombosis (DVT) was defined by Doppler ultrasound of the lower extremities, which revealed thrombosis. Thrombin-antithrombin complex (TAT), thrombomodulin (TM), and plasmin-antiplasmin complex (PIC) concentration were tested from each patient's preoperative and postoperative days 1, 4, 7, 14. These values were then accessed via receiver operating characteristic (ROC) curve analysis and further quantified the level of this risk by concentration. RESULTS: On postoperative day 1 (pod-1), all patients' TAT and PIC concentrations were significantly higher than those preoperatively (p < 0.05). The levels of TAT and PIC in patients in the DVT group on pod-1 were significantly higher than those in the non-DVT group (p < 0.05). At pod-1, the TAT concentration for DVT patients was 49.47 ng/mL compared to 20.70 ng/mL for non-DVT patients, PIC was 3.72µg/mL compared to 1.65µg/mL. ROC curve analysis demonstrated that a TAT concentration of 24.3 ng/mL had a sensitivity of 87.9% and a specificity of 69.1%. CONCLUSION: TAT levels on pod-1 may predict DVT early after THA/TKA, which makes it possible for early intervention to decrease the incidence of DVT.

Reliability and Validity of Standing Lateral Radiograph Method for Measuring Acetabular Component Version: A Modified Cross-table Lateral Radiograph Method.

OBJECTIVES: To investigate the effect of the X-ray incidence angle on cup version measurements and the reliability and validity of standing lateral (SL) radiography for measuring cup versions. METHODS: Cup versions under different X-ray incidence angles were investigated by the 3D simulation analysis. Ninety-three patients, who underwent primary total hip arthroplasty (THA) with postoperative SL radiographs and CT scans between April 2020 and December 2021, were retrospectively analyzed. SL radiography was taken under naturally standing position, correcting for the measurement error of pelvic tilt in cross-table lateral (CL) radiography. Cup versions were measured on SL radiographs and CT images by two qualified orthopedic physicians. The intra- and inter-observer reliabilities were assessed by intra-class correlation coefficient. The consistency between radiographic and CT measurements was evaluated using Pearson correlation coefficient. RESULTS: No significant differences in cup version measurements were observed between groups of different X-ray incidence angles (P = 0.663) in the 3D simulation analysis. All measurements had excellent intra- and inter-observer reliabilities, with an intraclass correlation coefficient of >0.95. Mean cup version measurements from SL radiographs correlated well with those from CT scans (r = 0.853, P < 0.001). The mean difference between radiographic and CT measurements was -0.49° (range -12.62° to 10.37°, SD 3.95°), and the majority of differences were within the 95% limits of agreement. CONCLUSION: The cup versions measured with SL radiography were close to the CT measurements. SL radiograph method is reliable and valid for measuring acetabular component version after THA.

Single-cell RNA sequencing reveals the cell types heterogenicity of human discoid lateral meniscus cells.

Discoid lateral meniscus (DLM) is more prone to injury than a normally shaped meniscus. No study has compared the gene expression and cell heterogeneity between discoid and normal menisci. We aimed to identify specific cell clusters and their marker genes in discoid meniscus, thereby providing a theoretical basis for the treatment and etiology of DLM. ScRNA-seq was used in DLM and osteoarthritis lateral meniscus (OAM) cells to identify cell subsets and their gene signatures. Pseudo-time analysis and immunohistochemical staining were used to investigate the temporal and spatial distribution of DLM-specific clusters. ScRNA-seq identified nine clusters originating from DLM and OAM, composed of seven empirically defined populations and two novel populations specific to DLM, namely, the prehypertrophic chondrocyte 2 (PreHTC-2) and regulatory chondrocyte (RegC-2) populations. Single-cell trajectory showed that RegC-2 and PreHTC-2 were mainly distributed in a specific cell fate, with the PreHTC-2 marker gene HAPLN1 highly expressed at the end of this fate. Immunohistochemical staining showed that HAPLN1 + cells were mainly distributed in the white zone of DLM. Matrix metalloproteinase (MMP) variants were expressed in DLM and OAM, with MMP2 highly expressed in OAM-dominant cell clusters, while MMP3 was highly expressed in DLM-dominant cell clusters. We concluded that two novel cell clusters including PreHTC-2 were identified using single-cell sequencing, which were mainly distributed in the white areas of DLM. Differentiated MMP expression in the trajectory may be a possible mechanism of DLM formation.

Avascular necrosis under different treatment in children with developmental dysplasia of the hip: a network meta-analysis.

The objective of this study was to evaluate the incidence of avascular necrosis (AVN) of the femoral head in children less than 3 years of age with developmental dysplasia of the hip (DDH) treated with closed reduction, open reduction alone and open reduction combined with osteotomy. We reviewed clinical trials from the PubMed, EMBASE and Cochrane Library databases (up to November 2020) that were related to closed reduction, open reduction alone and open reduction combined with osteotomy for the treatment of children under 3 years of age with DDH. The screening and quality evaluation of the literature were performed independently by two researchers. In case of disagreement, a third researcher resolved the discourse. Finally, the data were extracted, and the R software and GeMTC program package were used to conduct a network meta-analysis (NMA). The evaluation index was the incidence of AVN. Fourteen articles were included. The NMA showed that in terms of the incidence of AVN, cases treated with open reduction alone were higher than those with closed reduction, and the difference was statistically significant. Open reduction alone had the highest probability (94.4%) of having the highest incidence of AVN, followed by open reduction combined with osteotomy (5.5%) and closed reduction (0.1%). In the treatment of children with DDH who are younger than 3 years old, open reduction alone is most likely to be the treatment with the highest incidence of AVN, followed by open reduction combined with osteotomy. The closed reduction had the smallest probability of AVN.

Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors.

Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)-enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. We show that miR-328a-3p and miR-150-5p, enriched in the sEVs after TBI, promote osteogenesis by directly targeting the 3'UTR of FOXO4 or CBL, respectively, and hydrogel carrying miR-328a-3p-containing sEVs efficiently repaires bone defects in rats. Importantly, increased fibronectin expression on sEVs surface contributes to targeting of osteoprogenitors in bone by TBI sEVs, thereby implying that modification of the sEVs surface fibronectin could be used in bone-targeted drug delivery. Together, our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.

3D simulation of radiographic projections to test and reduce the effect of pelvic tilt on the accuracy of cross-table lateral radiography.

BACKGROUND: Cross-table lateral (CL) radiography is a convenient and feasible method to assess cup version angle (VA) after total hip arthroplasty; However, pelvic tilt (PT) may contribute to its measurement inaccuracy. How PT affects CL radiographic measurements have not been well studied. We sought (1) to determine the effect of the PT on cup version measurement on CL radiography and (2) to develop a method for reducing measurement errors caused by the PT. METHODS: We used 3D technique to construct standard model and capture CL radiography simulation. A linear regression model was created to analyze the relationship between PT and VA. CL radiography and computed tomography (CT) were performed for the enrolled patients after surgery. The consistency between CL and CT measurements were verified by intra-class correlation coefficient (ICC). RESULTS: There was a high correlation between the VA and PT. For each 1-degree increased in the PT, the VA decreased by 0.76° (R2 = 0.995, p < 0.001). Based on the data, we created a corrective formula to convert the radiographic measurements into values approximating the actual VA under a natural pelvic position. The VA measurements corrected by our equation was in high agreement with the CT-measured values with reference to the corresponding PT (ICC = 0.988, p < 0.001), which was in sharp contrast to that without PT control (ICC = 0.454, p = 0.203). CONCLUSIONS: The PT may contribute to cup version measurement inaccuracies on CL radiography. Our mathematical algorithm can serve as a reliable method to improve the accuracy of CL radiography.

Exosomal lncRNAs NONMMUT000375.2 and NONMMUT071578.2 derived from titanium particle treated RAW264.7 cells regulate osteogenic differentiation of MC3T3-E1 cells.

Periprosthetic osteolysis and the subsequent aseptic loosening can lead to the failure of joint replacement. Wear particles are well known to be the initiative cause inducing osteolysis through enhancing osteoclast-mediated bone resorption and reducing osteogenic differentiation. The purpose of this study was to investigate the effects of osteoclast-secreted exosomal long noncoding RNAs (lncRNAs) on osteogenesis in the process of particle-induced osteolysis. RAW264.7 cells were treated by titanium particles (TI). The inflammatory cytokines were increased, and expression of Receptor Activator of Nuclear Factor-κB and Nuclear factor of activated T cells c1 were also increased, indicating osteoclast differentiation occurred. The purified exosomes from RAW264.7 cells induced with TI inhibited osteogenic differentiation of MC3T3-E1 cells. RNA sequencing generated lncRNAs expression profiles (458 up-regulated and 1641 down-regulated) of the exosomes derived from RAW264.7 cells treated with TI. Based on the results of gene ontology/Kyoto Encyclopedia of Genes and Genomes analysis and quantitative real time polymerase chain reaction validation, we confirmed two candidate lncRNAs, NONMMUT000375.2 and NONMMUT071578.2. The regulation network presented that some vital genes involved in osteoclast differentiation, such as Bcl2, Wnt11, TGF-ß, and Pdk1, were under the regulation of NONMMUT000375.2 and NONMMUT071578.2. Taken together, exosomes derived from TI treated RAW264.7 cells inhibit the osteogenic activity of MC3T3-E1 cells. Exosomal lncRNAs, NONMMUT000375.2 and NONMMUT071578.2 may potentially play their roles in promoting osteoclast differentiation and suppressing osteogenesis, which aggravates the osteoclastogenesis/osteogenesis imbalance.

Prognostic value of enhancement rate by enhanced ultrasound in hepatitis B virus-positive hepatocellular carcinoma undergoing radiofrequency ablation.

AIM: To assess the prognostic significance of enhancement rate (ER) measured by contrast-enhanced ultrasonography (CEUS) in patients with hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). MATERIALS AND METHODS: A total of 253 patients with single primary HCC undergoing preoperative CEUS and RFA were enrolled in this study. The ER were evaluated though pretreatment CEUS. After a mean follow-up of 36.8 ± 10.2 months, the correlation of ER measured by CEUS and survival after RFA was analyzed by univariate and multivariate analysis. The optimal cutoff ER value to predict survival was determined using receiver-operating characteristic analysis. RESULTS: Mean follow-up period for all 253 patients was 36.8 ± 10.2 months, 31.2% of patients had died at endpoint. The optimal cutoff ER value predicting survival was 2.2 dB/s. Univariate analysis demonstrated that patients with a high ER level had poorer OS (62.8 months vs 48.8 months, P = 0.02) and recurrence-free survival (RFS = 60.2 months vs 47.4 months, P = 0.03) than patients with a low ER level. ER measured by CEUS also been confirmed as independent risk factor for overall survival (hazard ratio [HR], 1.87; 95% confidence interval [95% CI], 1.21-7.25; P < 0.01) and RFS (HR, 1.67; 95% CI, 1.08-6.21; P < 0.01) in multivariate analysis enrolling gender, BMI, tumor size, antiviral therapy, HBV DNA, histological differentiation, Child-Pugh score and tumor node metastasis (TNM) stage. CONCLUSIONS: ER measured by CEUS was a significant predictive factor for survival after RFA for HCC.

Wear particles enhance autophagy through up-regulation of CD147 to promote osteoclastogenesis.

OBJECTIVES: The study aimed to uncover the underlying mechanism linking wear particles to osteoclast differentiation, and we explored the effect of titanium particles of different sizes on CD147 expression and autophagy in macrophages. MATERIALS AND METHODS: Effects of titanium particles on CD147 and RANKL mRNA were detected by QPCR; protein level of CD147 and Beclin-1 were detected by Western blot; soluble RANKL were detected by ELISA. To determine the effect of CD147 and autophagy, KG-1a cells were transfected with siRNA-CD147 or treated with autophagy inhibitor CQ (chloroquine), and then co-cultured with different sizes of titanium particles. RESULTS: Our results showed that 0.2-1.2 µm and 1.2-10 µm titanium particles up-regulate CD147 to activate autophagy, which increase the level of soluble RANKL to promote osteoclastogenesis. Suppression of CD147 with siRNA could diminish particle-induced autophagy and soluble RANKL expression. In addition, CQ could dramatically reduce particle-induced soluble RANKL expression. CONCLUSION: Our findings suggested a possible mechanism underlying wear debris-induced osteolysis and identified CD147 as a potential therapeutic target in aseptic loosening.

An integrative analysis of DNA methylation in osteosarcoma.

BACKGROUND: The study aimed to analyze aberrantly methylated genes, relevant pathways and transcription factors (TFs) in osteosarcoma (OS) development. METHODS: Based on the DNA methylation microarray data GSE36002 that were downloaded from GEO database, the differentially methylated genes in promoter regions were identified between OS and normal samples. Pathway and function enrichment analyses of differentially methylated genes was performed. Subsequently, protein-protein interaction (PPI) network was constructed, followed by identification of cancer-associated differentially methylated genes and significant differentially methylated TFs. RESULTS: A total of 1379 hyper-methylation regions and 169 hypo-methylation regions in promoter regions were identified in OS samples compared to normal samples. The differentially hyper-methylated genes were significantly enriched in Neuroactive ligand-receptor interaction pathway, and Peroxisome proliferator activated receptor (PPAR) signaling pathway. The differentially hypo-methylated genes were significantly enriched in Toll-like receptor signaling pathway. In PPI network, signal transducers and activators of transcription (STAT3) had high degree (degree=21). MAX interactor 1, dimerization protein (MXI1), STAT3 and T-cell acute lymphocytic leukemia 1 (TAL1) were significant TFs enriched with target genes in OS samples. They were found to be cancer-associated and hyper-methylated in OS samples. CONCLUSION: Neuroactive ligand-receptor interaction, PPAR signaling, Toll-like receptor signaling pathways are implicated in OS. MXI1, STAT3, and TAL1 may be important TFs involved in OS development.

Deficient zinc levels and myocardial infarction : association between deficient zinc levels and myocardial infarction: a meta-analysis.

The purpose of this study is to clarify the association between Zn levels and myocardial infarction (MI) using a meta-analysis approach. We searched articles in the PubMed, OVID, and ScienceDirect published as of November 2014. Thirteen eligible articles with 2886 subjects from 41 case-control studies were identified. Overall, pooled analysis indicated that subjects with MI had lower Zn levels than healthy controls (standardized mean difference (SMD) = -1.848, 95 % confidence interval (CI) = [-2.365, -1.331]). Further subgroup analysis found that subjects with MI had lower Zn levels than healthy controls in serum (SMD = -1.764, 95 % CI = [-2.417, -1.112]) and hair (SMD = -3.326, 95 % CI = [-4.616, -2.036]), but not in toenail (SMD = -0.396, 95 % CI = [-1.114, 0.322]). The subgroup analysis stratified by type of Zn measurement found a similar pattern in inductively coupled plasma-atomic absorption spectrometry (ICP-AAS) (SMD = -2.442, 95 % CI = [-3.092, -1.753]), but not in neutron activation analysis (NAA) (SMD = -0.449, 95 % CI = [-1.127, 0.230]). Lower Zn levels in MI patients were found both in male (SMD = -3.350, 95 % CI = [-4.531, -2.169]) and female (SMD = -2.681, 95 % CI = [-3.440, -1.922]). And the difference of Zn levels according to MI in Asia (SMD = -2.555, 95 % CI = [-3.267, -1.844]) was greater to that among the population in Europe (SMD = -0.745, 95 % CI = [-1.386, -0.104]), but no difference was found in Oceania (SMD = -0.255, 95 % CI = [-0.600, 0.089]). In conclusion, this meta-analysis indicates that there is a significant association between Zn deficiency and MI. We suggest that a community-based, long-term observation in a cohort design should be performed to obtain better understanding of causal relationships between Zn and MI, through measuring hair Zn at baseline to investigate whether the highest zinc category versus lowest was associated with MI risk.