Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the diagnosis of rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a common autoimmune disease. However, the positive diagnosis value of the current biomarkers is unsatisfactory. Here, we aimed to identify RA-associated susceptibility genes and explore their potential as novel biomarkers for the diagnosis of RA. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy controls and RA patients. RNA-seq and bioinformatics analyses were performed to identify the hub genes associated with RA. Then, the expression of hub genes was assessed in mRNA expression profiles from GEO datasets. Real time-quantitative PCR (RT-qPCR) was performed to further confirm the expression of the hub genes using the PBMCs that were collected from RA patients (n=47) and healthy controls (n=40). Finally, we evaluated the diagnostic potential of the candidate mRNAs. RESULTS: RNA-seq analyses revealed 178 dysregulated genes measured by changes in mRNAs between the healthy controls and the RA patients. We identified 3 candidate mRNAs, including ASPM, DTL and RRM2, all of which were highly expressed in RA. RRM2 showed a significant higher expression in remissive RA compared with active RA. Significant correlations were observed between DTL and IL-8, TNF-α which were tested in serum by ELISA, between RRM2 and CDAI, DAS-28, tender and swollen joints, respectively. The expression level of RRM2 was significantly higher in RA patients with the Anti-CCP- than with the Anti-CCP+. The AUC (RA vs. OA) value of RRM2 was 0.941 (p<0.0001; sensitivity=0.867; specificity=0.904). CONCLUSIONS: RRM2 showed high diagnosis efficiency for RA patients. Therefore, the findings provided a novel candidate biomarker for the diagnosis of RA.

The change of cervical spine alignment along with aging in asymptomatic population: a preliminary analysis.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: To investigate the correlation of cervical spine alignment changes with aging in asymptomatic population. BACKGROUND: Previous studies demonstrated the influence of lumbar and thoracic spine on cervical spine alignment, but few has reported the cervical spine alignment change along with aging in asymptomatic population. METHODS: Asymptomatic population were divided into four groups according to different ages (Group A: ≤20 years; Group B: 21-40 years; Group C: 41-60 years; Group D: ≥61 years). Each group was composed of 30 subjects. The following parameters were measured: C0-1 Cobb angle, C1-2 Cobb angle, C2-7 Cobb angle, C1-7 sagittal vertical axis (C1-7 SVA), C2-7 SVA, central of gravity to C7 sagittal vertical axis (CG-C7 SVA), Thoracic Inlet Angle (TIA), Neck Tilt (NT), cervical tilt, cranial tilt, T1 slope (TS), TS-CL, and ANOVA statistical method was used to analyze the differences among four groups, and then, linear regression analysis was performed to analyze correlation of the cervical spine alignment with the aging. RESULTS: C1-7 SVA, C2-7 SVA, CG-C7 SVA, TIA, NT, TS, and cranial tilt were found statistically different among four groups (P < 0.01). From Group A to Group D, the mean C1-7 SVA were 30.7, 26.0, 21.8, and 36.9 mm, the mean C2-7 SVA were 18.7, 14.7, 11.9, and 24.7 mm, and the mean CG-C7 SVA were 19.6, 16.6, 9.4, and 26.7 mm. The mean TIA were 62.4°, 65.0°, 71.8°, and 76.9°, the mean NT were 39.4°, 43.8°, 46.3°, and 48.2°, the mean TS were 23.0°, 21.1°, 25.5°, and 28.7°, and the mean cranial tilt were 5.7°, 4.8°, 3.0°, and 9.5°. Further linear regression indicated that TIA (r = 0.472; P < 0.0001), NT (r = 0.337; P = 0.0006), and TS (r = 0.299; P = 0.0025) were positively correlated with aging. CONCLUSION: A gradual increase of TIA, NT, and TS, accompanied with an increased CL, is found along with aging in asymptomatic population, among which TIA, NT, and TS are significantly correlated with physiological nature of aging.

Débridement and Reconstruction Improve Postoperative Sagittal Alignment in Kyphotic Cervical Spinal Tuberculosis.

BACKGROUND: Cervical spinal tuberculosis is relatively common in some developing countries. It erodes vertebrae and discs, which sometimes results in cervical kyphosis and myelopathy. However, to our knowledge, no studies have evaluated improvements to patient-reported outcomes among patients who undergo surgical cervical sagittal realignment after kyphotic cervical spinal tuberculosis has been treated by débridement and reconstruction. QUESTIONS/PURPOSES: (1) Can a spine with kyphotic cervical spinal tuberculosis be returned to normal alignment and fused successfully? (2) Will patient-reported outcomes be improved with this intervention? (3) Are patient-reported outcomes correlated with realignment? METHODS: Forty-six patients with kyphotic cervical spinal tuberculosis were evaluated in this retrospective study. We generally performed surgery on patients with this condition when patients with cervical spinal tuberculosis presented with cervical kyphosis with or without neurologic deficits. Patients who did not meet these criteria were treated with other surgical procedures during the study period. Study patients were evaluated with cervical imaging, patient-reported outcomes questionnaires (Neck Disability Index [NDI], and the Japanese Orthopaedic Association [JOA] score), and physical examinations. Scores were collected by fellows preoperatively and at followup. No patient died during the followup. The mean followup was 26.8 months (range, 20-35 months). Preoperative and 2-year followup radiologic parameters were measured, including C0-2 Cobb angle, C2-7 Cobb angle, C2-7 sagittal vertical axis, center of gravity (CG) to C7 sagittal vertical axis (CG-C7 sagittal vertical axis), thoracic inlet angle, T1 slope, and neck tilt. The correlations between cervical alignment and the NDI and JOA score were analyzed. Factors correlated with the NDI and JOA score improvements were identified by multiple stepwise regression analysis. CT was used to assess bone fusion after surgery. RESULTS: All 46 patients showed bone fusion on CT scans. The preoperative C0-2 Cobb angle improved after surgery (mean difference, 5.0°; 95% CI, 2.3°-7.7°; p = 0.0068), as did C2-7 Cobb angle (mean difference, -33°; 95% CI, -35° to -31°; p = 0.0074), C2-7 sagittal vertical axis (mean difference, -28 mm; 95% CI, -30 mm to -26 mm; p = 0.0036), CG-7 sagittal vertical axis (mean difference, -26 mm; 95% CI, -28 mm to -24 mm; p = 0.0049), T1 slope (mean difference, 6.0°; 95% CI, 3.7°-8.3°; p = 0.0053) and the thoracic inlet angle (mean difference, 8.0°; 95% CI, 3.7°-12°; p = 0.0072). With the numbers available, the neck tilt angle did not improve (mean difference, -0.2°; 95% CI, -1.0° to 0.6°; p = 0.079). The preoperative NDI of 34 ± 5.1 decreased to 17 ± 4.6 (p = 0.0096) at followup. Improvements in NDI were correlated with the magnitude of correction of the cervical deformities, including C0-2 Cobb angle (r = -0.357, p = 0.007), C2-7 Cobb angle (r = 0.410, p = 0.002), T1 slope (r = -0.366, p = 0.006, thoracic inlet angle (r = -0.376, p = 0.005), C2-7 sagittal vertical axis (r = 0.450, p = 0.001), and CG-C7 sagittal vertical axis (r = 0.361, p = 0.007). The JOA score improved to 13 ± 2.6 from 7.2 ± 1.9, which did not correlate with postoperative cervical realignment. After controlling for potential confounding variables like Cobb angles and T1 slope, we found C2-7 sagittal vertical axis was the most influential factor correlated with NDI improvement (r = 0.450, p = 0.002). CONCLUSION: When treating kyphotic cervical spinal tuberculosis by débridement, decompression, and reconstruction, more attention should be drawn to realigning the cervical spine, in particular to restoring the C2-7 sagittal vertical axis. However, how best to restore the C2-7 sagittal vertical axis and cervical alignment in a kyphotic cervical spine needs further study. LEVEL OF EVIDENCE: Level III, therapeutic study.

The accuracy of the lateral vertebral notch-referred pedicle screw insertion technique in subaxial cervical spine: a human cadaver study.

STUDY DESIGN: This is a cadaver specimen study to confirm new pedicle screw (PS) entry point and trajectory for subaxial cervical PS insertion. OBJECTIVE: To assess the accuracy of the lateral vertebral notch-referred PS insertion technique in subaxial cervical spine in cadaver cervical spine. BACKGROUNDS: Reported morphometric landmarks used to guide the surgeon in PS insertion show significant variability. In the previous study, we proposed a new technique (as called "notch-referred" technique) primarily based on coronal multiplane reconstruction images (CMRI) and cortical integrity after PS insertion in cadavers. However, the PS position in cadaveric cervical segment was not confirmed radiologically. Therefore, the difference between the pedicle trajectory and the PS trajectory using the notch-referred technique needs to be illuminated. METHODS: Twelve cadaveric cervical spines were conducted with PS insertion using the lateral vertebral notch-referred technique. The guideline for entry point and trajectory for each vertebra was established based on the morphometric data from our previous study. After 3.5-mm diameter screw insertion, each vertebra was dissected and inspected for pedicle trajectory by CT scan. The pedicle trajectory and PS trajectory were measured and compared in axial plane. The perforation rate was assessed radiologically and was graded from ideal to unacceptable: Grade 0 = screw in pedicle; Grade I = perforation of pedicle wall less than one-fourth of the screw diameter; Grade II = perforation more than one-fourth of the screw diameter but less than one-second; Grade III = perforation more than one-second outside of the screw diameter. In addition, pedicle width between the acceptable and unacceptable screws was compared. RESULTS: A total of 120 pedicle screws were inserted. The perforation rate of pedicle screws was 78.3% in grade 0 (excellent PS position), 10.0% in grade I (good PS position), 8.3% in grade II (fair PS position), and 3.3% in grade III (poor PS position). The overall accepted accuracy of pedicle screws was 96.7% (Grade 0 + Grade I + Grade II), and only 3.3% had critical breach. There was no statistical difference between the pedicle trajectory and PS trajectory (p > 0.05). Compared to the pedicle width (4.4 ± 0.7 mm) in acceptably inserted screw, the unacceptably screw is 3.2 ± 0.3 mm which was statistically different (p < 0.05). CONCLUSION: The accuracy of the notch-referred PS insertion in cadaveric subaxial cervical spine is satisfactory.

ATG9A as a potential diagnostic marker of intervertebral disc degeneration: Inferences from experiments and bioinformatics analysis incorporating sc-RNA-seq data.

BACKGROUND: Disfunctional autophagy plays a pivotal role in Intervertebral Disc Degeneration (IDD) progression. however, the connection between Autophagy-related gene 9A (ATG9A) and IDD has not been reported. METHODS: Firstly, transcriptome datasets from the GEO and Autophagy-related genes (ARGs) from GeneCards were carried out using R. Following this, IDD-specific signature genes were identified through methods such as least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) analyses. Validation of these findings proceeded through in vitro experiments, evaluation of independent datasets, and analysis of receiver operating characteristic (ROC) curves. Subsequent steps incorporated co-expression analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), and construction of competing endogenous RNA (ceRNA) network. The final section established the correlation between immune cell infiltration, ATG9A, and IDD utilizing the CIBERSORT algorithm and single-cell RNA (scRNA) sequencing data. RESULTS: Research identified 87 differentially expressed genes, with only ATG9A noted as an IDD signature gene. Analysis of in vitro experiments and independent datasets uncovered a decrease in ATG9A expression within the degeneration group. The area under the curve (AUC) of ATG9A exceeded 0.8 following ROC analysis. Furthermore, immune cell infiltration and scRNA sequencing data analysis elucidated the substantial role of immune cells in IDD progression. A ceRNA network was constructed, centered around ATG9A, included 4 miRNAs and 22 lncRNAs. CONCLUSION: ATG9A was identified as a diagnostic gene for IDD, indicating its viability as a effective target for therapy disease.

The Correlation of Global Spinal Realignment With the Quality of Life After Corrective Surgery for Delayed Thoracolumbar Osteoporotic Fracture-Related Kyphosis.

BACKGROUND AND OBJECTIVES: Few studies have been conducted to evaluate the precise impact of corrective surgery on sagittal spinal realignment and clinical outcomes in cases of delayed thoracolumbar osteoporotic fracture-related kyphosis. To assess the efficacy of corrective surgery on sagittal spinal alignment and investigate the relationship between spinal alignment and health-related quality of life (HRQoL) in patients with delayed thoracolumbar osteoporotic fracture-related kyphosis. METHODS: A total of 78 patients were enrolled. The characteristics and surgical variables were meticulously documented. The sagittal spinal parameters were measured, and the HRQoL was evaluated using Oswestry Disability Index (ODI), SF-12 Physical Component Score (SF-12 PCS), and Scoliosis Research Society-22 Patient Questionnaire (SRS-22) before and after surgery. The changes in spinal parameters and HRQoL were analyzed through the paired t -test. The Pearson correlation analysis was performed to analyze the correlation of parameters with HRQoL. Then, a multiple stepwise regression analysis was performed with HRQoL scores as the dependent variable and spinal parameters as the independent variable. RESULTS: The operative time was 185.9 ± 33.2 min, and the estimated blood loss was 782.8 ± 145.2 mL. The results of the paired t -test revealed a significant difference preoperatively and at the final follow-up in the thoracic kyphosis, thoracolumbar kyphosis (TLK), lumbar lordosis, T9 tilt, pelvic tilt, sacral slope, sagittal vertical axis, and spinosacral angle as well as the ODI, SF-12 PCS, and SRS-22 ( P < .05). Multiple stepwise regression analysis revealed that TLK and pelvic tilt, TLK and sagittal vertical axis, and TLK were the primary parameters affecting the ODI, SF-12 PCS, and SRS-22, respectively. CONCLUSION: Corrective surgery can effectively realign the global spine and improve HRQoL in patients with delayed thoracolumbar osteoporotic fracture-related kyphosis. The change of TLK is a driving factor to realign the global spine.

Ferrostatin-1 facilitated neurological functional rehabilitation of spinal cord injury mice by inhibiting ferroptosis.

BACKGROUND: To seek the potential therapy for spinal cord injury, Ferrostatin-1, the first ferroptosis inhibitor, was administrated in spinal cord injury mice to identify the therapeutic effect. METHODS: Spinal cord injury model was established by a modified Allen's method. Then, ferrostatin-1 was administrated by intraspinal injection. Cortical evoked motor potential and BMS were indicated to assess the neurological function rehabilitation. H&E, Nissl's staining, NeuN, and GFAP immunofluorescence were used to identify the histological manifestation on the mice with the injured spinal cord. Spinosin, a selective small molecule activator of the Nrf2/HO-1 signaling pathway, was administrated to verify the underlying mechanism of ferrostatin-1. RESULTS: Ferrostatin-1 promoted the rehabilitation of cortical evoked motor potential and BMS scores, synchronized with improvement in the histological manifestation of neuron survival and scar formation. Spinosin disturbed the benefits of ferrostatin-1 administration on histological and neurobehavioral manifestation by deranging the Nrf2/HO-1 signaling pathway. CONCLUSIONS: Ferrostatin-1 improved the rehabilitation of spinal cord injury mice by regulating ferroptosis through the Nrf2/HO-1 signaling pathway.

Improvement of Pulmonary Function and Reconstructed 3-Dimensional Lung Volume After Halo-Pelvic Traction Combined With Posterior Correction for Severe Rigid Spinal Scoliosis: A Multicenter Study.

BACKGROUND AND OBJECTIVES: Severe rigid spinal scoliosis (SRSS) leads to severe restrictive ventilation dysfunction. Currently, the reports about the influence of preoperative halo-pelvic traction (HPT) combined with correction surgery on pulmonary function in patients with SRSS were relatively few. This study aims to investigate (1) the influence of preoperative HPT on lung volume and pulmonary function, (2) the further influence of the following correction surgery on lung volume and pulmonary function, and (3) the relationship among deformity correction, pulmonary function test outcomes, and computed tomography-based lung volume. METHODS: A total of 135 patients with SRSS who underwent preoperative HPT and followed low-grade osteotomy correction surgery were reviewed. Spinal parameters, including proximal thoracic curve, main thoracic curve (MTC), lumbar curve, coronal balance, thoracic kyphosis, lumbar lordosis, sagittal vertical axis, pulmonary function test outcomes (forced vital capacity [FVC], the percentage of predicted forced vital capacity [FVC%], forced expiratory volume in 1 second [FEV1], total lung capacity [TLC]), and lung volume (Vin), were analyzed before, after HPT and at the final follow-up, respectively. RESULTS: The mean FVC, FVC%, FEV1, and TLC increased from 1.67 L, 51.13%, 1.47 L, and 2.37 L to 1.95 L, 64.35%, 1.75 L, and 2.78 L, respectively, after HPT and further improved to 2.22 L, 72.14%, 1.95 L, and 3.15 L, respectively, at the final follow-up. The mean Vin increased from 1.98 L to 2.42 L after traction and further increased to 2.76 L at the final follow-up. The variation of MTC was correlated with the improvement of FVC (r = 0.429, P = .026), FVC% (r = 0.401, P = .038), FEV1 (r = 0.340, P = .043), and TLC (r = 0.421, P = .029) and the variation of Vin (r = 0.425, P = .015) before HPT and after surgery. CONCLUSION: Preoperative HPT can improve preoperative pulmonary function and enhance the preoperative lung volume. There were significant correlations among the variations of MTC, pulmonary function indexes, and lung volume before HPT and after surgery in patients with SRSS.

CircRNA expression profile and potential role of hsa_circ_0040039 in intervertebral disc degeneration.

PURPOSE: Circular RNAs (circRNAs) play an critical role in the pathological processes associated with IDD. However, the potential roles of circRNAs in IDD remain largely unclear. Here, we identify the circRNAs expression profiles and elucidate the potential role of candidate circRNAs in the pathogenesis of intervertebral disc degeneration (IDD) through microarray data and bioinformatics analyses. METHODS: We obtained the datasets of microarrays (GSE67566 and GSE116726) from the Gene Expression Omnibus database. The differentially expressed circRNAs and miRNAs were identified using the Limma R package. The target miRNAs and target genes of the candidate circRNAs were predicted using an online tool. Functional enrichment analyses of the target genes were performed using the clusterProfiler R package. A protein-protein interaction (PPI) network was constructed using STRING. RESULTS: A total of 104 differentially expressed circRNAs were identified between the IDD and the control groups, including 41 upregulated circRNAs and 63 downregulated circRNAs (cutoff criteria (|log2 fold change| > 2, P < .05)). Hsa_circ_0040039, which was the most upregulated circRNA (log2 fold change = 2.95), was selected for further analysis. The regulatory circRNA-miRNA-mRNA network comprised hsa_circ_0040039, 2 target miRNAs (hsa-miR-424-5p and hsa-miR-15b-5p), and 77 target genes. Functional enrichment analysis showed that the 77 promising target genes are mainly enriched in the ubiquitin proteasome system and Wnt signaling pathway. Further, the PPI network showed that the top 3 hub genes are BRTC, SIAH1, and UBE2V1. CONCLUSIONS: A total of 104 differentially expressed circRNAs were identified between the IDD and control groups. Hsa_circ_0040039 may serve as a sponge of hsa-miR-424-5p and hsa-miR-15b-5p, to regulate the expression of downstream genes (such as BRTC, SIAH1, and UBE2V1); thus, it may be involved in IDD-associated pathological processes via the Wnt/ß-catenin signaling pathway. Further studies are required to confirm the potential roles of hsa_circ_0040039 in IDD.

Global Spinal Realignment After Osteotomized Debridement in Active Lumbar Spinal Tuberculosis: Correlation with Patient-Reported Outcomes.

OBJECTIVE: Osteotomized debridement (OD) has been proved to be highly effective in treating active thoracolumbar tuberculosis (TB); however, no research has investigated how OD affects spinal alignment. The goal of this study was to explore the global alignment compensatory mechanism after lumbar OD, as well as the correlation between spinopelvic parameters and patient-reported outcomes (PROs). METHODS: Sixty-two patients with active lumbar spinal TB who underwent OD surgery were included. Spinopelvic parameters (C2-7 Cobb angle [C2-7 CA], sagittal vertical axis [SVA], proximal thoracic kyphosis, thoracic kyphosis, lumbar lordosis [LL], sacral slope [SS], pelvic tilt [PT], pelvic incidence [PI], spinosacral angle, and PI minus LL [PI-LL]) and PROs (Oswestry Disability Index [ODI] and Visual Analog Scale [VAS] score) were reviewed. The correlation between spinopelvic realignment and improved PROs was evaluated. RESULTS: Compared with preoperative measurements, C2-7 CA, proximal thoracic kyphosis, thoracic kyphosis, LL, SS, and spinosacral angle significantly increased after OD, whereas SVA, PT, and PI-LL significantly decreased. ODI and VAS score significantly improved postoperatively. The improvement of VAS was observed to be correlated with variations of C2-7 CA, SVA, LL, and PI-LL. The improvement of ODI was found to be correlated with variations of SVA, LL, and PI-LL. The multiple stepwise regression analysis showed that LL was an independent predictor for ODI and VAS score. CONCLUSIONS: The whole spine and pelvis are involved in realignment after lumbar spinal OD, which is closely related to PROs. More attention should be drawn to restoring an appropriate LL in lumbar TB surgery.

Posterior Approach With Osteotomized Debridement Versus Combined Anterior and Posterior Approach in Treating Thoracolumbar Tuberculosis: A Retrospective Cohort Study.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: To compare outcomes of posterior osteotomized debridement (OD) with combined anterior and posterior approach (AP) in treating thoracolumbar tuberculosis (TB). METHODS: This study reviewed 178 patients who were diagnosed as active thoracolumbar TB and surgically treated in our center. One hundred and two patients underwent posterior OD, interbody fusion with titanium mesh cage (TMC), and instrumentation (group A). Seventy-six patients underwent one-stage posterior instrumentation, anterior debridement, and interbody fusion with TMC (group B). Patients' clinical outcomes were compared between the 2 groups. RESULTS: Erythrocyte sedimentation rate and C-reactive protein in all patients returned to normal levels within 3 months after surgery, and no recurrence occurred during the follow-up. Compared with AP approach, OD surgery was less invasive and with a lower cost (¥ 70 581 ± 17 645 vs ¥ 87 600 ± 27 328; P < .05). Patients treated by OD showed more significant improvements in Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) than those treated by AP approach 3 months postoperatively (VAS: 3.0 ± .7 vs 3.7 ± .9; ODI: 14.7 ± 4.4 vs 20.6 ± 4.6). Two groups showed similar postoperative kyphosis correction and final follow-up correction loss (P = .361 and P = .162, respectively). The OD method had a lower complication rate than AP approach (9.8% [10/102] vs 35.5% [27/76]; P < .05). CONCLUSIONS: Posterior OD is effective in treating active thoracolumbar TB. Compared with traditional AP approach, OD surgery has less surgical invasiveness, lower complication rate, and shorter fusion time.

CircHIPK3 prevents chondrocyte apoptosis and cartilage degradation by sponging miR-30a-3p and promoting PON2.

Osteoarthritis (OA) is a common joint disease featured by the deterioration of articular cartilage and chondrocyte death. Emerging evidence has indicated that circular RNAs (circRNAs) play an essential role in OA progress. Here, we found that the expression of circHIPK3 was significantly decreased in human and mouse OA cartilage. Knocking down circHIPK3 increased apoptosis and intracellular ROS level in HC-a chondrocytes. We performed proteomic studies and identified that circHIPK3 regulated chondrocyte apoptosis through the mitochondrial pathway. Results of JC-1 staining and western blot further confirmed that mitochondrial outer membrane permeabilization was promoted in HC-a chondrocytes transfected by circHIPK3 siRNA. In terms of mechanism, we showed that PON2 functioned as a potential target of circHIPK3 to regulate chondrocyte apoptosis. Moreover, we revealed that circHIPK3 interacted with miR-30a-3p to regulate PON2 expression in chondrocytes. Taken together, our findings suggested that circHIPK3 regulated chondrocyte apoptosis by mitochondrial pathway, and targeting the circHIPK3/miR-30a-3p/PON2 axis might be a potential strategy for OA treatment.

Exploring the Mystery of Osteoarthritis using Bioinformatics Analysis of Cartilage Tissue.

BACKGROUND: Osteoarthritis (OA) is a kind of chronic disease relating to joints, which seriously affectsthe daily life activities of the elderly and can also lead to disability. However, the pathogenesis of OA is still unclear, which leads to limited treatment and the therapeutic effect far from people's expectations. This study aims to filter out key genes in the pathogenesis of OA and explore their potential role in the occurrence and development of OA. METHODS: The dataset of GSE117999 was obtained and analyzed in order to identify the differentially expressed genes (DEGs), hub genes and key genes. We also identified potential miRNAs which may play a major role in the pathogenesis of OA, and verified their difference in OA by real-time quantitative PCR (RT-qPCR). DGldb was found to serve as an indicator to identify drugs with potential therapeutic effects on key genes and Receiver Operating Characteristic (ROC) analysis was used for identifying underlying biomarkers of OA. RESULTS: We identified ten key genes, including MDM2, RB1, EGFR, ESR1, UBE2E3, WWP1, BCL2, OAS2, TYMS and MSH2. Then, we identified hsa-mir-3613-3p, hsa-mir-548e-5p and hsamir- 5692a to be potentially related to key genes. In addition, RT-qPCR confirmed the differential expression of identified genes in mouse cartilage with or without OA. We then identified Etoposide and Everolimus, which were potentially specific to the most key genes. Finally, we speculated that ESR1 might be a potential biomarker of OA. CONCLUSION: In this study, potential key genes related to OA and their biological functions were identified, and their potential application value in the diagnosis and treatment of OA has been demonstrated, which will help us to improve the therapeutic effect of OA.

Clock knockdown attenuated reactive oxygen species-mediated senescence of chondrocytes through restoring autophagic flux.

AIMS: Articular cartilage degeneration has been recognized as the primary pathological change in osteoarthritis (OA). Mechanisms that govern the shift from cartilage homeostasis to OA remain unknown. Previous studies have reported that intrinsic circadian clock in chondrocytes could function to optimize cartilage repair/remodeling to optimum times of day, but little is known about its molecular mechanisms. This study attempted to investigate the potential role and mechanism of circadian gene Clock in OA pathology. MATERIALS AND METHODS: The expression of Clock in OA chondrocytes and cartilage was detected by qRT-PCR, western blot and immunohistochemistry. Temporal gene expression changes were analyzed using qRT-PCR in chondrocytes transfected with siClock following dexamethasone synchronization. In addition, the effect of Clock knockdown on senescent phenotypes and autophagic flux was evaluated in chondrocytes treated with siClock or siCntrl. KEY FINDINGS: The expression of Clock was up-regulated in OA cartilage from humans and mouse models. Clock knockdown had no influence on rhythmic expression of the downstream genes in primary chondrocytes. We also found that Clock knockdown elevated antioxidant enzyme activities, diminished reactive oxygen species (ROS) production and attenuated senescence of chondrocytes via restoring autophagic flux. SIGNIFICANCE: Clock knockdown can attenuate ROS-mediated senescence of chondrocytes through restoring autophagic flux in non-circadian manner, providing a potential therapeutic target for OA.

Identification of circular RNAs hsa_circ_0140271 in peripheral blood mononuclear cells as a novel diagnostic biomarker for female rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease, which commonly affects women. Accumulating evidence shows that differentially expressed circular RNAs (circRNAs) play crucial roles in the progress of RA. However, the roles of circRNAs in female RA remains unclear. This study explores potential role and diagnostic value of hsa_circ_0140271 from peripheral blood mononuclear cells (PBMC) in female RA. METHODS: Differential expression of circRNAs was determined by RNA-sequencing in PBMC from 4 healthy controls (HC) and 4 RA patients, and we further measured the level of hsa_circ_0140271 in a validation cohort consisting of 47 RA and 47 HC via RT-qPCR. Besides, correlation studies with clinical variables were also examined. What's more, we performed bioinformatics analysis to predict the potential role of hsa_circ_0140271. RESULTS: PBMC expression of hsa_circ_0140271 of female RA was significantly higher than that of female HC, and it was positively correlated with antistreptolysin (ASO). Furthermore, the receiver operating characteristic (ROC) curve indicated that hsa_circ_0140271 could distinguish female RA from female HC and female patients with ankylosing spondylitis (AS) or osteoarthritis (OA). Besides, the combined diagnosis anti-cyclic citrullinated peptide (Anti-CCP) + hsa_circ_0140271 could improve diagnostic accuracy with an area under the curve (AUC) of 0.818 to compared with Anti-CCP. Furthermore, KEGG pathway enrichment analysis indicated hsa_circ_0140271 may act as microRNA sponge and participate in fatty acid metabolism pathways. CONCLUSION: Hsa_circ_0140271 was likely to be used as a promising diagnostic biomarker for female RA; it may act as microRNA sponge to regulate fatty acid metabolism pathways in RA.

Gene Expression Profiling Analysis to Identify Key Genes and Underlying Mechanisms in Meniscus of Osteoarthritis Patients.

BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of life of elderly. Regrettably, the pathological mechanism for OA has not yet been fully elucidated. METHODS: This study is committed to distinguishing key genes and the underlying mechanisms for OA. Raw data was acquired from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs), hub genes, and key genes through bioinformatics analysis. Subsequently, we predicted the microRNAs (miRNAs) and circular RNAs (circRNAs) associated with these key genes that may play key roles in OA using web tools. We also constructed a protein- drug network and found potentially effective drugs by analyzing the relationships between the drugs and the key genes. RESULTS: The analysis revealed 360 DEGs, 24 hub genes, and 15 key genes enriched in many categories potentially related to the pathological mechanism of OA. hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were predicted to be important miRNAs for OA, while hsa_circ_0025119, hsa_circ_0025113, hsa_circ_0009897, and hsa_circ_0002447 were predicted to be the most important circRNAs. Further studies indicated that Ocriplasmin and Collagenase clostridium histolyticum may be effective drugs for the treatment of OA. Finally, CD34 and VWF were inferred to be the most meaningful biomarkers for OA. CONCLUSION: In conclusion, we determined the underlying key genes, miRNAs, and circRNAs for OA, predicted potentially effective drugs, and identified the most meaningful biomarkers for the disease. Our findings may provide insight into the pathological mechanism of OA and guide future research.

Comprehensive expression profiles of CircRNAs, LncRNAs, and mRNAs in PBMCs from patients with the ossification of the posterior longitudinal ligament

Ossification of the posterior longitudinal ligament (OPLL), one of spinal disease causing myelopathy, is characterized by the ectopic ossification and narrowing of the spinal cord. However, the pathogenesis of OPLL is largely unclear. In this study, transcriptome expression profiles (circRNAs, lncRNAs, and mRNAs) were identified via high-throughput sequencing using peripheral blood mononuclear cells (PBMCs) from OPLL and non-OPLL patients. We found that 1150 mRNAs, 331 circRNAs, and 1429 lncRNAs were significantly differentially expressed in the PBMCs of OPLL patients. GO and KEGG enrichment analyses revealed that most mRNAs were associated with inflammation. The co-expression networks indicated that circRNAs and lncRNAs could regulate the mRNAs through influencing the inflammation of OPLL. The circRNA-miRNA-mRNA integrated network showed that circRNA-regulated mRNAs associated with TGF-ß and TNF-α signaling pathways. These analyses indicate that circRNAs, lncRNAs, and mRNAs from PBMCs might contribute to inflammation in OPLL.

Diagnostic and therapeutic values of PMEPA1 and its correlation with tumor immunity in pan-cancer.

AIMS: The prostate transmembrane protein, androgen induced 1 (PMEPA1) is differentially expressed in pan-cancer. However, PMEPA1 specific role in cancers has not been fully clarified. This study aims to explore the potential role of Pmepa1 in pan-cancer and specific cancer, with a view to deepening the research on the pathological mechanism of cancer. MAIN METHODS: The Perl language and R language were used to identify the correlation between PMEPA1 expression level and clinical indicators, prognosis values, tumor microenvironment, immune cells' infiltration, immune checkpoint genes, TMB and MSI. The Therapeutic Target Database was used for identifying potential therapeutic drugs that target the pathways that are significantly affected by PMEPA1 expression. KEY FINDINGS: PMEPA1 differential expression significantly correlated with patients' age, race, tumors' stage and status. PMEPA1 high expression was closely correlated with poor prognosis in many cancer types, excluding prostate adenocarcinoma. PMEPA1 expression was closely related to tumor cells and the immune microenvironment in stromal and immune cells' level, immune cells' infiltration, immune checkpoint genes, tumor mutational burden and microsatellite instability. We also found that the activity of the olfactory transduction pathway was closely related to PMEPA1 expression. In pan-cancer, Trifluoperazine and Halofantrine have the potential to reduce PMEPA1 expression. SIGNIFICANCE: This study integrated existing data to explore PMEPA1 potential function in cancers, provided insights for the future cancer-related studies.

Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies.

BACKGROUND: Knee osteoarthritis (OA) is a major cause of disability in the elderly, however, there are few studies to estimate the global prevalence, incidence, and risk factors of knee OA. METHODS: For this study, we searched PUBMED, EMBASE and SCOPUS from inception to April 4, 2020, without language restriction. We identified eligible studies with information on the prevalence or incidence of knee OA in population-based observational studies and extracted data from published reports. We did random-effects meta-analysis to generate estimates. This study was registered with PROSPERO (CRD42020181035). FINDINGS: Out of 9570 records identified, 88 studies with 10,081,952 participants were eligible for this study. The pooled global prevalence of knee OA was 16⋅0% (95% CI, 14⋅3%-17⋅8%) in individuals aged 15 and over and was 22⋅9% (95% CI, 19⋅8%-26⋅1%) in individuals aged 40 and over. Correspondingly, there are around 654⋅1 (95% CI, 565⋅6-745⋅6) million individuals (40 years and older) with knee OA in 2020 worldwide. The pooled global incidence of knee OA was 203 per 10,000 person-years (95% CI, 106-331) in individuals aged 20 and over. Correspondingly, there are around annual 86⋅7 (95% CI, 45⋅3-141⋅3) million individuals (20 years and older) with incident knee OA in 2020 worldwide. The prevalence and incidence varied substantially between individual countries and increased with age. The ratios of prevalence and incidence in females and males were 1⋅69 (95% CI, 1⋅59-1⋅80, p<0⋅00) and 1⋅39 (95% CI, 1⋅24-1⋅56, p<0⋅00), respectively. INTERPRETATION: Our study provides the global prevalence (16⋅0% [95% CI, 14⋅3%-17⋅8%]) and incidence (203 per 10,000 person-years [95% CI, 106-331]) of knee OA. These findings can be used to better assess the global health burden of knee OA. Further prospective cohort studies are warranted to identify modifiable risk factors for providing effectively preventive strategies in the early stages of the disease. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (nos. 81772384 and 81572174).