Osteoarthritis (OA) is a chronic degenerative disease resulting joint disability and pain. Accumulating evidences suggest that chondrocyte extracellular matrix calcification plays an important role in the development of OA. Here, we showed that Krüppel-like factor 10 (Klf10) was involved in the regulation of chondrocyte extracellular matrix calcification by regulating the expression of Frizzled9. Knockdown of Klf10 attenuated TBHP induced calcification and reduced calcium content in chondrocytes. Restoring extracellular matrix calcification of chondrocytes could aggravate chondrocyte senescence. Destabilization of a medial meniscus (DMM) mouse model of OA, in vivo experiments revealed that knockdown Klf10 improved the calcification of articular cartilage and ameliorated articular cartilage degeneration. These findings suggested that knockdown Klf10 inhibited extracellular matrix calcification-related changes in chondrocytes and alleviated chondrocyte senescence.

AIM:This study aimed to evaluate the miR-223-5p expression in patients with spinal cord injury (SCI) and to determine its role in the pathogenesis of SCI. METHODS:The serum miR-223-5p levels were analyzed using quantitative real-time polymerase chain reaction. The diagnostic accuracy of miR-223-5p was evaluated using the receiving operating characteristic curves. LPS-induced PC12 cells were established as an in vitro inflammatory cell model. Cell apoptosis, inflammation and oxidative stress were examined. The SCI rat model was constructed to evaluate the effects of miR-223-5p on inflammatory response and motor function in rats. RESULTS:MiR-223-5p expression was upregulated in SCI patients. MiR-223-5p expression in the complete SCI group was significantly higher than that in incomplete SCI group. ROC analysis showed that miR-223-5p can distinguish SCI patients from healthy volunteers. In vitro experiments demonstrated that LPS upregulated apoptosis and inflammation in PC12 cells. Treatment with miR-223-5p inhibitor alleviated the changes in LPS-induced PC12 cells . Inhibition of miR-223-5p can alleviate the activation of inflammatory response and the effects of SCI on the motor function in rats. CONCLUSIONS:MiR-223-5p is a potential diagnostic marker for SCI, and it can promote the SCI progression by regulating nerve cell survival, inflammation, and oxidative stress.

BackgroundEwing sarcoma (ES) is a common primary bone tumor in children. Our study aimed to compare overall survival (OS) between pediatric and adult bone ES patients, identify independent prognostic factors and develop a nomogram for predicting OS in adult patients with ES of bone.MethodsWe retrospectively analyzed data for the 2004–2015 period from the Surveillance, Epidemiology, and End Results (SEER) database. To guarantee well-balanced characteristics between the comparison groups, propensity score matching (PSM) was used. Kaplan–Meier (KM) curves were used to compare OS between pediatric and adult patients with ES of bone. Univariate and multivariate Cox regression analyses were used to screen independent prognostic factors for ES of bone, and a prognostic nomogram was constructed by using the factors identified. The prediction accuracy and clinical benefit were evaluated using receiver operating characteristic (ROC) curves, areas under the curves (AUCs), calibration curves, and decision curve analysis (DCA).ResultsOur results showed that adult ES patients had lower OS than younger ES patients. Age, surgery, chemotherapy, and TNM stage were independent risk factors for bone ES in adults and were used to develop a nomogram. AUCs for 3-, 5-, and 10-year OS were 76.4 (67.5, 85.3), 77.3 (68.6, 85.9) and 76.6 (68.6, 84.5), respectively. Calibration curves and DCA results indicated excellent performance for our nomogram.ConclusionWe found that ES pediatric patients have better OS than adult ES patients, and we constructed a practical nomogram to predict the 3-, 5- and 10-year OS of adult patients with ES of bone based on independent prognostic factors (age, surgery, chemotherapy, T stage, N stage and M stage).

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.

Long non-coding RNAs show essential roles in various cancer processes. This study aimed at the expression features, prognosis significance, and biological effect of lnc MATN1-AS1 in osteosarcoma (OS). Five kinds of cell lines and 117 pairs of tissues were analyzed by qRT-PCR for quantification of lnc MATN1-AS1 and miR-1299 level. Clinical data were analyzed using Chi-Square Tests to show the association with lnc MATN1-AS1 level. Kaplan–Meier analysis and Cox regression were used to judge the prognostic value. Cell counting kit-8 and Transwell assay were conducted, respectively, to analyze the effect of lnc MATN1-AS1 on cell proliferation and metastasis. The target miRNA was predicted. lnc MATN1-AS1 level was significantly elevated in OS cells and tissues and related to Enneking staging, lung metastasis, and histologic type. Patients with high lnc MATN1-AS1 level showed a shorter overall survival and recurrence-free survival. Lnc MATN1-AS1 knockdown inhibited OS cell proliferation, migration, and invasion by sponging miR-1299. Lnc MATN1-AS1 has oncogenic features and prognostic significance in OS and is a novel therapeutic strategy for OS.

Objective. To investigate the expression of long-chain noncoding RNA GAS5 in osteoarthritis(OA) and the effect of silencing GAS5 on autophagy of osteoarthritis chondrocytes (OACs). Methods. OA rat models were constructed by cutting the anterior cruciate ligament, and the expressions of GAS5 in rat cartilage tissues at 4 weeks (early OA) and 12 weeks (late OA) after modeling were detected. The rat chondrocytes were isolated, cultured and transfected with si-GAS5 to silencing GAS5. Then, the changes of apoptosis and autophagy levels of OA chondrocytes were detected by transfection of GFP-LC3 and flow cytometry. Bioinformatic tools were used to analyze the miRNA binding to GAS5 and the downstream target genes, then luciferase reporter assay and GDC-0349 (inhibitor of mTOR) were used to verify their relationships. Results. The expression of GAS5 in cartilage tissue of OA rats was higher than control, which was higher in late OA than that in early OA. After silencing the GAS5, the autophagy ability of OACs was increased and the apoptosis rate was decreased. GAS5 was able to bind to miR-144 and regulate the expressin of mTOR. mTOR inhibitor GDC-0349 could reverse the inhibition of GAS5 on autophagy but could not reverse its effect on apoptosis. Conclusion. GAS5 expresses highly in OA cartilage tissues and increases with the progression of OA. GAS5 inhibits autophagy and promotes the apoptosis of OACs, and the inhibition of autophagy may be related to its regulation of mTOR.

Ramp lesion of the medial meniscus used to be completely disregarded in the past. Ramp lesion has been now put under the spotlight by orthopaedic and sport medicine surgeons and requires attention. It is closely associated with anterior cruciate ligament injury. Major risk factors include chronic laxity, lateral meniscal lesion, anterior cruciate ligament reconstruction revision, anterolateral ligament tear concomitant with anterior cruciate ligament injury, time from injury, pre-operative side-to-side laxity > 6 mm, age < 30 years old, male sex, etc. Radiologists attempt to create diagnostic criteria for ramp lesion using magnetic resonance imaging. However, the only definite method to diagnose ramp lesion is still arthroscopy. Various techniques exist, among which posteromedial approach is the most highly recommended. Various treatment options are available. The success rate of ramp repair is very high. Major complications are uncommon. Cite this article: EFORT Open Rev 2021;6:372-379. DOI: 10.1302/2058-5241.6.200126

Objective 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-alpha 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).Conclusion RRM2 showed high diagnosis efficiency for RA patients. Therefore, the findings provided a novel candidate biomarker for the diagnosis of RA.

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the recent study by Kovalic et al.(1) showing that patients with severe/critical COVID‐19 may have elevated liver biochemistries. We found that there are some potential methodological pitfalls. First, the authors searched only three databases, which may not be enough to collect all the eligible studies. Since the outbreak of COVID‐19, many studies have been uploaded to preprint websites, such as the Social Science Research Network, bioRxiv, and medRxiv. Omitting these important grey literature publications may lead to exaggerated estimates of pooled effects.(2) Additionally, although the meta‐analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, the protocol was not preregistered in any platforms, such as the Cochrane Library and the International Prospective Register of Systematic Reviews, which may affect its transparency and reproducibility. Second, the authors analyzed publication bias and concluded that there was not significant publication bias in the included studies. It may be inappropriate, however, to use funnel plots or Egger’s test to assess publication bias when there are fewer than 10 studies.(3) In the Methods section, the authors stated that the fixed‐effects model was used when no significant heterogeneity was found (I2 < 50%). However, we are confused because some of the pooled results (I2 < 50%) shown in figures 2A and 3 were calculated using the random‐effects model. Third, accumulating evidence indicated that chronic liver diseases (CLDs) were independent prognostic factors for patients with COVID‐19.(4) Therefore, it would be better to evaluate the influence of different stages of CLDs on liver biochemistries in subgroup analysis, which may contribute to risk stratification and individualized treatments for patients with COVID‐19. Additionally, the pooled results of the current meta‐analysis were based on 6 studies with a total of 586 patients, so the potential “small‐sample effect” or “false‐positive effect” cannot be excluded. Consequently, the conclusions should be interpreted with caution, and this limitation should be stated in the Discussion section. We respectfully thank Kovalic et al for providing us with valuable work. Considering the potential methodological flaws, further studies with better scientific designs are warranted to elucidate this problem.

The current study was aimed at exploring the potential roles and possible mechanisms of miR-10a-5p in osteoarthritis (OA). We performed RT-qPCR, Western blot, CCK8, EdU Assay, and flow cytometry assay to clarify the roles of miR-10a-5p in OA. Furthermore, the whole transcriptome sequencing together with integrated bioinformatics analyses were conducted to elucidate the underlying mechanisms of miR-10a-5p involving in OA. Our results demonstrated that miR-10a-5p was upregulated in OA and acted as a significant contributing factor for OA. A large number of circRNAs, lncRNAs, miRNAs, and mRNAs were identified by overexpressing miR-10a-5p. Functional enrichment analyses indicated that these differentially-expressed genes were enriched in some important terms including PPAR signaling pathway, PI3K-Akt signaling pathway, and p53 signaling pathway. A total of 42 hub genes were identified in the protein-protein interaction network including SERPINA1, TTR, APOA1, and A2M. Also, we constructed the network regulatory interactions across coding and noncoding RNAs triggered by miR-10a-5p, which revealed the powerful regulating effects of miR-10a-5p. Moreover, we found that HOXA3 acted as the targeted genes of miR-10a-5p and miR-10a-5p contributed to the progression of OA by suppressing HOXA3 expression. Our findings shed insight on regulatory mechanisms of miR-10a-5p, which might provide novel therapeutic targets for OA.

[This retracts the article DOI: 10.2147/OTT.S256617.].

Backgroud: Osteoarthritis (OA) is a common disease caused by chondrocyte dysfunction. KLF10 is a member of the Spl -like transcription factor family that is involved in regulating osteoblasts, but its expression and regulatory mechanism(s) in chondrocytes are unclear. In the present study, we aimed to investigate the regulatory role of KLF10 on the pathological process of OA. Methods: KLF10 expression in the cartilaginous tissue of patients with osteoarthritis (OA) was evaluated by immunohistochemistry (IHC). Next, we generated an OA mouse model, and the histological changes in cartilage tissue were verified using H&E staining, Safranin O-Fast Green staining, and IHC assays. KLF10 expression in the articular chondrocytes of OA mice was determined by qRT-PCR and Western blotting. To investigate the role of KLF10 in regulating cell proliferation and migration, a KLF10 overexpression plasmid was constructed and transfected into primary mouse chondrocytes. Subsequently, we used RNA sequencing (RNA-seq) to screen differentially expressed genes in chondrocytes with or without KLF10 overexpression. qRT-PCR was used for verification purposes. Results: We found that KLF10 was upregulated in the cartilaginous tissue of patients with OA as well as in cartilaginous tissue of the OA mouse model. KLF10 overexpression inhibited the proliferation and migration of chondrocytes. Furthermore, RNA sequencing results identified increased expression of Acvr1 and decreased expression of Mhbb in cells overexpressing KLF10. Changes in mRNA expression of Acvr1 and Mhbb were confirmed by qRT-PCR. Conclusions: KLF10 inhibits chondrocyte proliferation and migration by regulating the expression of Acvr1 and Inhbb in both human and mouse OA. These data suggest that KLF10 may be a potential therapeutic target for the treatment of OA.

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 randomeffects 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. (C) 2020 The Author(s). Published by Elsevier Ltd.

Background: Metastasis is the leading cause of death for patients with osteosarcoma (OS). In the present study, we explore the biomarkers for metastatic OS and provide potential therapeutic approaches. Materials and Methods: RNA-Seq data and clinical follow-up information were downloaded from TARGET and GEO databases. A Cox regression model was used to analyze metastatic events. L1000FWD, DGIdb, and CMap databases were used to identify potential drugs related to metastasis. Invasion and migration transwell assays and an adhesion assay were used to identify biological functions of genes. Results: A total of 15 metastasis-related signatures (MRSs) were associated with the prognosis based on the TARGET or GSE21257 cohorts, among which IL10RA and TLR7 genes were especially significant. In the DGIdb drug–gene interaction database, TLR7 and IFNGR1 were found to have potential interactions with drugs. After inhibiting the expression of TLR7 , the migration, invasion, and adhesion ability of OS cells were significantly enhanced, which further promoted metastasis. Conclusion: We identified a set of MRS that may be related to OS metastases. Among them, TLR7 plays a vital role and may be a potential target for OS metastasis treatment.

Aging-related osteoarthritis (OA) is the most common type of arthritis. Chondrocyte senescence has been linked with the pathogenesis of OA. Here, we examined the expression of GPR39 in chondrocytes and its modulatory effect on IL-1β-induced cellular senescence. We show that GPR39 is moderately expressed in human chondrocytes and its expression is repressed by the pro-inflammatory cytokine IL-1β. The GPR39 agonist TC-G 1008 mitigates IL-1β-induced chondrocyte senescence. Mechanistically, we show that TC-G 1008 mitigates IL-1β-induced cell cycle arrest at G1 phase by suppressing the expression of p53, p21, PAI-1, and K382 acetylation of p53. Moreover, we show that TC-G 1008 treatment restores IL-1β-induced inhibition of SIRT1 and the silencing of SIRT1 abolishes the function of TC-G 1008 on p53 acetylation and senescence, suggesting that the function of GPR39 signaling is mediated by SIRT1 in chondrocytes. Altogether, our findings implicate that the activation of GPR39 signaling ameliorates IL-1β-induced chondrocyte senescence and the GPR39 agonist TC-G 1008 could have the potential to modulate aging-associated OA.

J Li, L Bao, ZJ Xia and KY Ding contributed equally to this study.