Enhancer variants on chromosome 2p14 regulating SPRED2 and ACTR2 act as a signal amplifier to protect against rheumatoid arthritis.

Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.

[Influence factors of deep venous thromboembolism after knee arthroplasty and significance of changes of serum nets and sVCAM-1 levels].

OBJECTIVE: To investigate the relationship between the changes of serum neutrophil extracellular traps (NETs), soluble vascular cell adhesion molecule-1(sVCAM-1) and deep venous thromboembolism after knee arthroplasty. METHODS: From May 2017 to April 2020, 30 patients with deep venous thromboembolism after knee arthroplasty were retrospectively selected as the observation group, and 60 patients without deep venous thromboembolism after knee arthroplasty in the same period were randomly selected as the control group. The clinical data, serum levels of nets and sVCAM-1 before and 1, 3 and 5 days after operation were compared between the two groups. Logistic regression model was used to analyze the influencing factors of deep venous thromboembolism after knee arthroplasty; Pearson correlation was used to analyze the relationship between serum nets and sVCAM-1 levels;Draw the receiver operating characteristic curve(ROC) to obtain the area under the curve(AUC), and analyze the diagnostic value of serum nets and sVCAM-1 levels for deep vein thromboembolism after knee arthroplasty. RESULTS: There were statistically significant differences between two groups in age, body mass index, and postoperative knee elevation and flexion ratio(P<0.05). The level of serum NETs and sVCAM-1 on the 1st and 3rd day after surgery of the observation group were higher than the control group(P<0.05). Logistic regression analysis showed that age, body mass index, knee flexion position, serum nets and sVCAM-1 levels at 1 and 3 days after operation were all the influencing factors of DVT after knee arthroplasty (P<0.05);Pearson correlation analysis showed that there was a positive correlation between the levels of serum NETs and sVCAM-1 in patients with deep venous thromboembolism after knee arthroplasty 1 and 3 days after operation(P<0.05). The ROC curve of predicting deep venous thromboembolism after knee arthroplasty by serum nets and sVCAM-1 levels at 1 and 3 days after operation was drawn, the results showed that the AUC of serum nets and sVCAM-1 levels at 1 day after operation was higher than that at 3 days after operation, which had a good predictive effect. CONCLUSION: The influencing factors of deep vein thromboembolism after knee arthroplasty are age, body mass index, postoperative knee elevation and flexion, postoperative serum NETs and sVCAM-1 levels, especially postoperative serum NETs and sVCAM-1 levels. Changes can be used as potential biomarkers for predicting postoperative deep vein thromboembolism, and clinical attention should be paid to it.

[Application of sliding osteotomy in total knee arthroplasty for patients with extra-articular femoral deformity].

OBJECTIVE: In order to observe the clinical effects of sliding osteotomy for patients with severe knee osteoarthritis and varus knee due to complex femoral extra-articular deformity to achieve the medial and lateral soft tissue balancing during total knee arthroplasty. METHODS: From June 2014 to January 2018, a total of 22 patients with severe knee osteoarthritis and complex extra-articular malformation of femurs were treated with total knee arthroplasty. There were 5 males and 17 females in this group, aged 48 to 76 years old, with an average age of (61.3±13.8) years old. All the patients had varus deformities caused by extra-articular deformities of femur. Hip-knee-ankle(HKA) angle was(158.8±9.7) ° before operation, and the average Knee Society Score (KSS) clinical score was 32.6±6.1;KSS function score was 35.8 ±9.6;the average Hospital for Special Surgical (HSS) score was 39.7±4.6;the average range of motion before operation was (80.6±10.7) °. The mechanical alignment method was used in joint replacement. The flexion space was balanced first. The coronal plane vertical sliding osteotomy was performed on the medial femoral condyle for the imbalance of coronal plane. The sliding distance of the osteotomy block was determined by straightening the gap between the inner and outer sides of the space until the space was balanced. After the separated segments were fixed with several screws, the prosthesis was installed as usual. RESULTS: The wounds of all patients healed in the first stage, and no wound complications occurred. All the 22 patients were followed up, and the duration ranged from 18 months to 3 years with an average of (28.2±10.1) months. X-ray showed that the fracture line disappeared for 2 to 5(3.5±1.5) months without nonunion. HKA angle measured at the latest follow up was (178.8±0.7) °, which wassignificantly different from that before operation. The HSS score was 91.3 ±6.0;KSS clinical score 93.7±3.5;KSS functional score 81.2±6.5;and the average range of motion of knee joint was(121.7±11.6) °, which was statistically significant compared with that before operation. CONCLUSION: For severe knee osteoarthritis patients with complex femoral extra-articular deformity, sliding osteotomy is performed. For severe varus deformity, downward sliding the medial femoral condyle is performed. The operation is relatively simple and the damage is small. It is easy to achieve the balance of internal and external soft tissue in flexion extension space. The short-term clinical effect is satisfactory.

Identification of Novel Target for Osteosarcoma by Network Analysis.

BACKGROUND Osteosarcoma (OS) is a highly complicated bone cancer involving imbalance of signaling transduction networks in cells. Development of new anti-osteosarcoma drugs is very challenging, mainly due to lack of known key targets. MATERIAL AND METHODS In this study, we attempted to reveal more promising targets for drug design by "Target-Pathway" network analysis, providing the new therapeutic strategy of osteosarcoma. The potential targets used for the treatment of OS were selected from 4 different sources: DrugBank, TCRD database, dbDEMC database, and recent scientific literature papers. Cytoscape was used for the establishment of the "Target-Pathway" network. RESULTS The obtained results suggest that tankyrase 2 (TNKS2) might be a very good potential protein target for the treatment of osteosarcoma. An in vitro MTT assay proved that it is an available option against OS by targeting the TNKS2 protein. Subsequently, cell cycle and apoptosis assay by flow cytometry showed the TNKS2 inhibitor can obviously induce cell cycle arrest, apoptosis, and mitotic cell death. CONCLUSIONS Tankyrase 2 (TNKS2), a member of the multifunctional poly(ADP-ribose) polymerases (PARPs), could be a very useful protein target for the treatment of osteosarcoma.

Hydroxytyrosol inhibits the inflammatory response of osteoarthritis chondrocytes via SIRT6-mediated autophagy.

Osteoarthritis (OA) is a common degenerative joint disease. Inflammation may exaggerate the catabolism and degeneration in the pathogenesis of OA. Hydroxytyrosol (HT) has been used in the management of inflammatory diseases. In addition, reports have revealed that autophagy was a therapeutic target of diseases caused by inflammation. Sirtuin 6 (SIRT6) has also been demonstrated to prevent OA development by reducing both the inflammatory response and chondrocyte senescence. However, the roles of SIRT6 and autophagy in cartilage and its underlying anti­inflammatory mechanism are unknown. Therefore, the present study aimed to determine the effects of HT on autophagy and inflammation in chondrocytes, and clarify whether HT regulates the inflammatory response through SIRT6­mediated autophagy. The expression of protein and mRNA were determined by western blot analysis and reverse transcription­quantitative polymerase chain reaction. The production of cytokines was detected by ELISA. It was demonstrated that HT inhibited the levels of interleukin (IL)­1ß and IL­6 in tumor necrosis factor (TNF)­α­stimulated chondrocytes in a concentration­dependent manner. In addition, HT promoted cell autophagy and increased the mRNA and protein expression levels of SIRT6 in chondrocytes stimulated with TNF-α. Autophagy inhibitor 3-methyladenine or knockdown of SIRT6 decreased the inhibitory effects of HT on the inflammatory response in chondrocytes. In addition, knockdown of SIRT6 attenuated the expression of microtubule-associated protein 1A/1B­light chain 3 and Beclin1 in chondrocytes. Overall, these findings suggested that HT inhibits the inflammatory response of chondrocytes through SIRT6­mediated autophagy. The present study provided a new drug target for the clinical treatment of inflammatory diseases.

High expression of TRIM29 (ATDC) contributes to poor prognosis and tumor metastasis by inducing epithelial­mesenchymal transition in osteosarcoma.

The association of TRIM29 overexpression with cancer progression and poor clinical prognosis has been reported in the context of several types of cancers. In the present study, we investigated the prognostic relevance of TRIM29 and its involvement in the progression of human osteosarcoma. To the best of our knowledge, this is the first study to demonstrate a major role of TRIM29 in osteosarcoma. Our results showed that the expression of TRIM29 in osteosarcoma tissues was much higher than that in normal bone tissues. Furthermore, TRIM29 expression was significantly correlated with tumor size, recurrence, metastasis and overall survival time. High expression of TRIM29 and presence of metastasis were independent predictors of poor prognosis in these patients. Both protein and mRNA expression of TRIM29 in osteosarcoma cell lines were significantly higher than those in osteoblast cell line, hFOB1.19. Moreover, the results indicated that TRIM29 promoted migration and invasive growth of osteosarcoma cells by inducing epithelial-mesenchymal transition. Therefore, ectopic expression of TRIM29 potentially contributes to metastasis and poor prognosis in patients with osteosarcoma. In summary, TRIM29 is a potential prognostic biomarker and a therapeutic target for patients with osteosarcoma.

Association of RECQL5 gene polymorphisms and osteosarcoma in a Chinese Han population.

Despite the knowledge on many genetic variants present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. RECQL is a DNA helicase involved in DNA mismatch repair and has been reported to be associated with many human cancers. We aimed to investigate the association of RECQL genetic polymorphism with osteosarcoma in a Chinese population. We selected three polymorphisms of the RECQL5 gene (rs820196, rs820200, and rs4789223) in the present study. TaqMan method was utilized for genotyping these three SNPs in 212 patients with osteosarcoma and 240 age- and sex-matched noncancer controls. In our study, we found that CC genotype in rs820196 (17.5 vs 8.3%, P = 0.005) and AA genotype in rs4789223 (21.7 vs 14.2, P < 0.001) were more frequent in osteosarcoma group compared to the control group, respectively. We also found that the C allele of rs820196 (OR = 1.492, 95% CI 1.138 ∼ 1.951; P = 0.004) and A allele of rs4789223 (OR = 1.767, 95% CI: 1.354 ∼ 2.301; P < 0.001) were common in the osteosarcoma patients than those in the control subjects, respectively. Haplotype analysis showed that TTA (OR = 3.469, 95% CI 1.798 ∼ 6.695; P < 0.001) was associated with increased risk for osteosarcoma. However, the TTG (OR = 0.578, 95% CI 0.442 ∼ 0.756) was associated with decreased risk for osteosarcoma. Our results suggested that RECQL5 genetic polymorphisms were associated with osteosarcoma in a Chinese population.