Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K-AKT pathway.

Synovial inflammation and fibrosis are important pathological changes associated with osteoarthritis (OA). Herein, we investigated if nintedanib, a drug specific for pulmonary fibrosis, plays a positive role in osteoarthritic synovial inflammation and fibrosis. We assessed the effect of nintedanib on osteoarthritic synovial inflammation and fibrosis in a mouse model of OA created by destabilization of the medial meniscus and a macrophage M1 polarization model created by stimulating RAW264.7 cells with lipopolysaccharide. Histological staining showed that daily gavage administration of nintedanib significantly alleviated articular cartilage degeneration, reduced the OARSI score, upregulated matrix metalloproteinase-13 and downregulated collagen II expression, and significantly reduced the synovial score and synovial fibrosis in a mouse OA model. In addition, immunofluorescence staining showed that nintedanib significantly decreased the number of M1 macrophages in the synovium of a mouse model of OA. In vitro results showed that nintedanib downregulated the phosphorylation levels of ERK, JNK, p38, PI3K, and AKT while inhibiting the expression of macrophage M1 polarization marker proteins (CD86, CD80, and iNOS). In conclusion, this study suggests that nintedanib is a potential candidate for OA treatment. The mechanisms of action of nintedanib include the inhibition of M1 polarization in OA synovial macrophages via the MAPK/PI3K-AKT pathway, inhibition of synovial inflammation and fibrosis, and reduction of articular cartilage degeneration.

Can Bisphosphonate Therapy Reduce Overall Mortality in Patients With Osteoporosis? A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: For patients with osteoporosis, bisphosphonate therapy can reduce the risk of fractures, but its effect on reducing mortality remains unclear. Previous studies on this topic have produced conflicting results and generally have been too small to definitively answer the question of whether bisphosphonate therapy reduces mortality. Therefore, a meta-analysis may help us arrive at a more conclusive answer. QUESTIONS/PURPOSES: In a large meta-analysis of placebo-controlled randomized controlled trials (RCTs), we asked: (1) Does bisphosphonate use reduce mortality? (2) Is there a subgroup effect based on whether different bisphosphonate drugs were used (zoledronate, alendronate, risedronate, and ibandronate), different geographic regions where the study took place (Europe, the Americas, and Asia), whether the study was limited to postmenopausal female patients, or whether the trials lasted 3 years or longer? METHODS: We conducted a systematic review using multiple databases, including Embase, Web of Science, Medline (via PubMed), Cochrane Library, and ClinicalTrials.gov, with each database searched up to November 20, 2023 (which also was the date of our last search), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We included randomized, placebo-controlled clinical trials with participants diagnosed with osteoporosis and receiving bisphosphonate treatment. We excluded papers posted to preprint servers, other unpublished work, conference abstracts, and papers that were registered on ClinicalTrials.gov but were not yet published. We collected 2263 records. After excluding records due to study type, study content not meeting the inclusion criteria, and duplicates, our meta-analysis included 47 placebo-controlled RCTs involving 59,437 participants. Data extraction, quality assessment, and statistical analyses were performed. The evaluation of randomized trials for potential bias was conducted using the revised Cochrane Risk of Bias tool. This assessment encompassed factors such as sequence generation, allocation concealment, subject blinding, outcome assessor blinding, incomplete outcome data, and reporting bias. Some studies did not provide explicit details regarding random sequence generation, leading to a high risk of selection bias. A few studies, due to their open-label nature, were unable to achieve double-blind conditions for both the subjects and the researchers, resulting in intermediate performance bias. Nevertheless, the overall study quality was high. Due to the low heterogeneity among the studies, as evidenced by the low statistical heterogeneity (that is, a low I2 statistic), we opted for a fixed-effects model, indicating that the effect size is consistent across the studies. In such cases, the fixed-effects model can provide more precise estimates. According to the results of the funnel plot, we did not find evidence of publication bias. RESULTS: The use of bisphosphonates did not reduce the overall risk of mortality in patients with osteoporosis (risk ratio 0.95 [95% CI 0.88 to 1.03]). Subgroup analyses involving different bisphosphonate drugs (zoledronate, alendronate, risedronate, and ibandronate), regions (Europe, the Americas, and Asia), diverse populations (postmenopausal female patients and other patients), and trials lasting 3 years or longer revealed no associations with reduced overall mortality. CONCLUSION: Based on our comprehensive meta-analysis, there is high-quality evidence suggesting that bisphosphonate therapy for patients with osteoporosis does not reduce the overall risk of mortality despite its effectiveness in reducing the risk of fractures. The primary consideration for prescribing bisphosphonates to individuals with osteoporosis should continue to be centered on reducing fracture risk, aligning with clinical guidelines. Long-term studies are needed to investigate potential effects on mortality during extended treatment periods. LEVEL OF EVIDENCE: Level I, therapeutic study.

Effectiveness of COVID-19 vaccines among children and adolescents against SARS-CoV-2 variants: a meta-analysis.

This systematic review and meta-analysis aimed to evaluate the effectiveness of COVID-19 vaccines among children and adolescents against SARS-CoV-2 variants. We searched PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov for studies published on or before June 20, 2023. Studies evaluating the effectiveness of COVID-19 vaccines in children and adolescents (≤ 18 years of age) were included. Data extraction, quality assessment, and analysis were conducted following PRISMA guidelines. Ten studies were included, comprising five cohort studies (527,778 participants) and four case-control studies (1,477,422 participants). The overall vaccine effectiveness (VE) against SARS-CoV-2 variants was 68% (95% CI = 60-74%). In terms of age, the VE was higher in adolescents aged 12-18 years [69%(95% CI = 61-75%)] than in children aged 5-11 years [44%(95% CI = 1-68%)]. "Fully vaccinated" may offer greater protection than "partially vaccinated," with a VE of 71% (95%CI = 59-79%) and 66% (95%CI = 51-76%), respectively.    Conclusion: This meta-analysis presents moderate-quality evidence that the COVID-19 vaccine is effective in safeguarding children and adolescents from the SARS-CoV-2 variant. Being fully vaccinated may offer greater protection than being partially vaccinated. Nevertheless, additional high-quality controlled trials are required to verify this finding. What is Known: • The COVID-19 pandemic has led to the rapid development and deployment of vaccines worldwide. Children and adolescents are a unique population for vaccination, and the effectiveness of vaccines against SARS-CoV-2 variants in this age group is of concern. What is New: • The COVID-19 vaccine is effective in protecting children and adolescents against the SARS-CoV-2 variant. Being fully vaccinated may offer greater protection than being partially vaccinated.

Biomechanical comparison of the femoral neck system versus InterTan nail and three cannulated screws for unstable Pauwels type III femoral neck fracture.

BACKGROUND: There are a variety of internal fixation methods for unstable femoral neck fractures (FNFs), but the best method is still unclear. Femoral neck system (FNS) is a dynamic angular stabilization system with cross screws, and is a new internal fixation implant designed for minimally invasive fixation of FNFs. In this study, we conducted a biomechanical comparison of FNS, InterTan nail and three cannulated screws for the treatment of Pauwels III FNFs and investigate the biomechanical properties of FNS. METHODS: A total of 18 left artificial femurs were selected and randomly divide into Group A (fixation with FNS), Group B (fixation with InterTan nail) and Group C (fixation with three cannulated screws), with 6 specimens in each group. After creating Pauwels type III FNF models, the specimens in each were tested with non-destructive quasi-static tests, including torsion, A-P bending and axial compression tests. The average slope of the linear load-deformation curve obtained from quasi-static tests defines the initial torsional stiffness, A-P bending stiffness, and axial compression stiffness. After cyclic loading test was applied, the overall deformation of models and local deformation of implant holes in each group were assessed. The overall deformation was estimated as the displacement recorded by the software of the mechanical testing apparatus. Local deformation was defined as interfragmental displacement. Data were analyzed by one-way analysis of variance (ANOVA) followed by Bonferroni post hoc test using the SPSS software (version 24.0, IBM, New York, NY, USA). Correlation analysis was performed using Pearson's correlation analysis. RESULTS: Group B exhibited significantly higher axial stiffness and A-P bending stiffness than the other two groups (P < 0.01), while Group A had significantly higher axial stiffness and A-P bending stiffness than Group C (P < 0.01). Groups A and B exhibited significantly higher torsional stiffness than Group C (P < 0.01), no statistical significance was observed between Groups A and B (P > 0.05). Group B exhibited significantly lower overall and local deformations than the other two groups (P < 0.01), while Group A had significantly lower overall and local deformations than Group C (P < 0.01). Correlation analysis revealed positive correlation between axial stiffness and A-P bending stiffness (r = 0.925, P < 0.01), torsional stiffness (r = 0.727, P < 0.01), between torsional stiffness and A-P bending stiffness; negative correlation between overall, local deformations and axial stiffness (r = - 0.889, - 0.901, respectively, both P < 0.01), and positive correlation between the two deformations (r = - 0.978, P < 0.01). CONCLUSION: For fixation of unstable FNFs, InterTan nail showed the highest axial stiffness and A-P bending stiffness, followed by FNS, and then three cannulated screws. Torsional stiffness of FNS was comparable to that of the InterTan nail. FNS, as a novel minimally invasive implant, can create good mechanical environment for the healing of unstable FNFs. Clinical studies are needed to confirm the potential advantages of FNS observed in this biomechanical study.

Osteoclasts secrete leukemia inhibitory factor to promote abnormal bone remodeling of subchondral bone in osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a common chronic degenerative joint disease. At present, there is no effective treatment to check the progression of osteoarthritis. Osteochondral units are considered to be one of the most important structures affecting the occurrence and development of osteoarthritis. Osteoclasts mediate an increase in abnormal bone remodeling in subchondral bone in the early stage of osteoarthritis. Here, alendronate (ALN) that inhibit osteoclasts was used to study the regulatory effect of osteoclast-derived leukemia inhibitory factor (LIF) on early abnormal bone remodeling. METHODS: This study involved 10-week-old wild-type female C57BL/6 mice and female SOST knockout (KO) mice that were divided into the sham, vehicle, ALN, and SOST KO groups. RESULTS: The expression of LIF was found to decrease by inhibiting osteoclasts, and the histological OA score suggested that the degeneration of articular cartilage was attenuated. Additionally, micro-CT showed that osteoclasts inhibited in the early stage of OA could maintain the microstructure of the subchondral bone. The parameters of bone volume fraction (BV/TV), subchondral bone plate thickness (SBP.Th), and trabecular separation (Tb.Sp) of the treated group were better than those of the vehicle group. CONCLUSIONS: These results suggested that downregulating the expression of sclerostin in osteocytes by secreting LIF from osteoclasts, activate the Wnt/ß-catenin signaling pathway, and promote abnormal bone remodeling in OA. Therefore, clastokine LIF might be a potential molecular target to promote abnormal bone remodeling in early OA.

Extensive cytokine analysis in synovial fluid of osteoarthritis patients.

OBJECTIVE: Osteoarthritis (OA) is a joint disease characterized by articular cartilage loss and afflicts many people worldwide. However, diagnostic methods and treatment options remain limited and are often characterized by low sensitivity and low efficacy. The focus of the present study was to identify proteomic biomarkers in synovial fluid to improve diagnosis and therapy of OA patients. METHODS: Antibody array technology was utilized for protein expression profiling of synovial fluid from 24 OA patients and 24 healthy persons. RESULTS: Compared with healthy persons, twenty proteins showed lower expression levels in OA patients, while thirty proteins had higher levels. Among these differential proteins, GITRL, CEACAM-1, FSH, EG-VEGF, FGF-4, PIGF, Cystatin EM and NT-4 were found for the first time to be differentially expressed in OA. Bioinformatics analysis showed that most of these differential proteins were involved leukocytes events, and some differentially expressed proteins including IL-18, CXCL1, CTLA4, MIP-3b, CD40, MMP-1, THBS1, CCL11, PAI-1, BAFF, aggrecan, angiogenin and follistatin were located in central positions of the protein-protein interaction (PPI) network. CONCLUSION: We speculate that leukocyte proliferation and migration to the joint may be an important pathogenesis of OA, which needs a further validation. The central proteins of the PPI network may play a more pivotal role in OA. The newly identified differentially expressed proteins may be novel biomarkers for OA diagnosis and targets for OA therapy.

The protective mechanism of SIRT1 on cartilage through regulation of LEF-1.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative disease that suppresses middle-aged and older people worldwide. Silent information regulator 1(SIRT-1) is associated with several age-related diseases, such as cardiovascular diseases, neurodegenerative diseases and tumors, etc. The protective role of SIRT-1 in bone and joint diseases has become increasingly well known. OBJECTIVE: To explore the relationship between SIRT-1 and its related factors in OA. METHODS: Fresh tibial plateau specimens were collected from 30 patients with knee OA who underwent total knee arthroplasty. According to the results of Safranin O Fast Green Staining, hematoxylin-eosin staining and the OARSI grade developed by the International Association for the Study of Osteoarthropathy, the specimens were divided into the mild group, moderate group and severe group, and the damage of cartilage was evaluated. SIRT-1 protein levels in cartilage samples were analyzed by immunohistochemistry. Then, take 60 8-week-old female C57BL/6 J mice and apply the Destabilization of the medial meniscus (DMM) to induce OA. Mice were randomly divided into normal group (sham), model group (model), and post-modeling drug administration group (srt), and each group was further divided into 2 weeks after modeling (2 W) and 8 weeks after modeling (8 W) according to the time after surgery. The degenerative degree of a knee joint in mouse knee cartilage samples was evaluated using Safranin O Fast Green Staining and OARSI grade. Immunohistochemical techniques assessed the protein levels of SIRT-1, ß-catenin, LEF-1, MMP-13 and Collagen II in cartilage samples. The protein levels of ß-catenin, LEF-1 and MMP-13 in the samples were assessed by the immunohistofluorescence technique. The mRNA expression of SIRT-1 and LEF-1 in mouse cartilage samples was evaluated by real-time quantitative polymerase chain reaction (qPCR). RESULTS: In the human cartilage samples, according to the results of Safranin O Fast Green Staining, compared with the mild group, the moderate group and the severe group showed damage cartilage layer structure, the number of chondrocytes decreased, the cell hypertrophic, the cartilage surface discontinuous, and the OARSI grade increased. The severe group had severe cartilage injury and the highest OARSI grade. In the mice cartilage samples, according to immunohistochemical analysis, the protein levels of ß-catenin, LEF-1 and MMP-13 in cartilage specimens of model 2 W and model 8 W groups were significantly increased than the sham 2 W and sham 8 W groups. The protein levels of SIRT-1 and Collagen II were significantly decreased (P < 0.05), the results of srt 2 W and srt 8 W groups were between the sham group and the model group. According to immunofluorescence analysis, the protein levels of ß-catenin, LEF-1 and MMP-13 in model 2 W and model 8 W groups were significantly increased than sham 2 W and sham 8 W groups. The results of srt 2w and srt 8w groups were between the sham group and the model group. According to the real-time qPCR results: Compared with sham 2 W and sham 8 W groups, the mRNA expression of SIRT-1 in model 2 W and model 8 W groups was significantly decreased, while the mRNA expression of LEF-1 was significantly increased. In contrast, the results of srt 2 W and srt 8 W groups were between the sham group and the model group. CONCLUSION: SRT-1720, as a specific activator of SIRT-1, does increase the protein level of SIRT-1. SIRT-1 may play a protective role in cartilage by regulating the expression of LEF-1 and related inflammatory factors in OA.

Irisin promotes osteogenic differentiation of bone marrow mesenchymal stem cells by activating autophagy via the Wnt//ß-catenin signal pathway.

Osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays a crucial role in osteoporosis. Irisin, an exercise-induced muscle-dependent myokine, has been reported to stimulate the development of brown adipose tissue and regulate energy expenditure. The present study aimed to investigate the effects of irisin on autophagy in BMSCs. Furthermore, the osteogenic differentiation ability was evaluated, as well as the activation of autophagy. It was found that 40 µM irisin for 48 h was an appropriate concentration and time period, with regards to cell viability, which was measured with a Cell Counting Kit-8. Moreover, the increasing expression levels of microtubule-associated protein light chain 3 (Lc3)-I/II and autophagy related 5 (Atg5) by irisin demonstrated the upregulation of autophagy. Mechanistically, bafilomycin A1 and Atg5 small interfering RNA were used to evaluate the possible mechanism of autophagy activated by irisin, and it was identified that irisin may upregulate autophagy by increasing the Atg12-Atg5-Atg16L complex. In addition, with the increasing level of autophagy, osteogenesis and the Wnt/ß-catenin signal pathway were also enhanced. However, inhibition of autophagy by bafilomycin A1 negatively regulated osteogenic differentiation. Collectively, the present results suggested that irisin may stimulate autophagy in BMSCs and that osteogenic differentiation may be enhanced by stimulating autophagy.

High-viscosity bone cement for vertebral compression fractures: a prospective study on intravertebral diffusion and leakage of bone cement.

BACKGROUND: Bone cement leakage causes severe complication following percutaneous vertebroplasty. This study probed the diffusion and leakage status of bone cement injected within diverged time duration, so as to find the optimal injection time for bone cement. METHODS: A total of 70 patients with osteoporotic vertebral compression fractures with a symptom of low back pain, who underwent treatment at hospital were enrolled in this study. Patients were randomized into three groups: < 180 s, 180-300, and > 300 s of injection time duration from the beginning to the completion of the injection. The scenarios of vertebral bone cement leakage and diffusion were inspected using postoperative CT. RESULTS: The diffusion coefficient was higher in group A than in group B whereas it was higher in group B than in group C, but without statistical significance among the three groups. The leakage rate was without statistical significance among the three groups. The injection time of bone cement was negatively correlated with the diffusion coefficient, at the correlation coefficient of - 0.253. CONCLUSIONS: The diffusion coefficient of high-viscosity bone cement is negatively correlated with the injection time, and the leakage rate of high-viscosity bone cement does not reduce with the prolongation of injection time.

Comparison of the efficacy of posterior-anterior screws, anterior-posterior screws and a posterior-anterior plate in the fixation of posterior malleolar fractures with a fragment size of ≥ 15 and < 15.

BACKGROUND: Different fixation methods have been used to treat posterior malleolar fractures (PMFs), but the clinical efficacy of different fixation methods in the treatment of PMF with different fragmentation has rarely been reported. The purpose of this study was to investigate the efficacy of posterior-anterior (PA), anterior-posterior (AP) screws and PA plate in the fixation of PMFs with a fragment size of ≥15 and < 15%. METHODS: This is a retrospective study of the clinical data of 243 patients with a unilateral ankle fracture involving the posterior malleolar ankle fracture. All patients were divided into two groups based on their fragment size, ≥15% (n = 136) and < 15% (n = 107). After reduction of PMF under direct vision via a posterolateral approach, posterior-anterior (PA), anterior-posterior (AP) screws and PA plate were used for fixation of PMF in the two groups. Briefly, for fixation of PMF with PA screw, two to three 3.5-mm (Depuy Synthes, Switzerland) cannulated screws were placed from the posterior to anterior direction; for fixation with PA plate, a 3.5-mm reconstruction plate (Depuy Synthes, Switzerland) was placed from the posterior to anterior direction, and for fixation of PMF with an AP screw, two to three 3.5-mm screws were placed from the anterior to posterior direction. All patients were followed up at 1, 3, 6, and 12 months after surgery and thereafter at 6-month intervals. The primary outcomes were AOFAS and ROM, which were recorded at the final follow-up. RESULTS: The average follow-up time for all patients was 18.9 months (range 12-36 months), and all fractures healed. In fragment size ≥15% group, the average AOFAS score of patients treated with PA, AP screws and posterior plate were 91.5, 91.8, and 90.8, respectively, and the average limited ankle-dorsiflexion ROM was 5.0 °, 5.4 ° and 5.6°, respectively, at the last follow-up, there was no significant difference between the three fixation methods in terms of AOFAS scores and ankle ROM (P > 0.05). In fragment size < 15% group, the average AOFAS score of patients treated with PA, AP screws and posterior plate were 92.3, 91.9, and 84.1, respectively, the average limited ankle-dorsiflexion ROM were 5.1 °, 4.7 °, and 6.3 °, respectively, at the last follow-up. There were statistically significant differences in AOFAS scores and ankle ROM between posterior plate fixation and PA, AP screw fixation (P < 0.05); while no significant difference was found between PA and AP screw fixation (P > 0.05). CONCLUSION: For PMFs with fragment size ≥15%, there was no significant difference in the outcomes between the three fixation methods. For PMF with fragmentation < 15%, the PA and AP screws both provided good fixation.

Rapamycin attenuates articular cartilage degeneration by inhibiting ß-catenin in a murine model of osteoarthritis.

Purpose: To investigate whether systemic injection of rapamycin attenuates articular cartilage degeneration by inhibiting ß-catenin in a murine model of osteoarthritis (OA). Materials and methods: Ten-week-old male C57BL/6j wild-type (WT) mice and SOST-knockout (SOST-/-) mice were randomized to a sham group, a vehicle-treated group, and a rapamycin-treated group. Mice in the vehicle-treated group underwent destabilizing of the medial meniscus (DMM) in the right knee, and were then treated with vehicle. Mice in the rapamycin treatment group underwent DMM and were treated with rapamycin. Safranin O-Fast green staining and Osteoarthritis Research Society International (OARSI) modified Mankin score were used to evaluate the histopathological features of the articular cartilage in the knee. The expression of light chain 3 (LC3) was evaluated by immunofluorescence, whereas the expression of ATG5, matrix metallopeptidase 13 (MMP-13), vascular endothelial growth factor (VEGF), sclerostin, and ß-catenin were evaluated by immunohistochemistry. TUNEL staining was used to determine apoptosis of chondrocytes. Results: In vehicle-treated mice when compared with mice in the sham group, the OARSI scores, expression of MMP-13, VEGF, sclerostin, ß-catenin, and chondrocyte apoptosis were significantly increased, whereas the expression of LC3 and ATG5 were significantly decreased. A systemic injection of rapamycin activated chondrocyte autophagy, which increased the expression of LC3 and ATG-5, and reduced OARSI scores, the expression of ß-catenin, MMP-13, and VEGF, and chondrocyte apoptosis in rapamycin treated mice when compared with vehicle-treated mice. Conclusions: Systemic injection of rapamycin attenuated articular cartilage degeneration by inhibiting ß-catenin in a murine model of OA.

Gremlin-1 Concentrations Are Correlated with the Severity of Knee Osteoarthritis.

BACKGROUND Gremlin-1, a bone morphogenetic protein (BMP) antagonist, is up-regulated in osteoarthritis (OA). Therefore, we aim to evaluate the correlation between gremlin-1 concentrations and the onset and severity of OA. MATERIAL AND METHODS We performed this cross-sectional study in a population of 212 patients with knee OA and 125 healthy controls. RESULTS Patients with knee OA had higher serum gremlin-1 concentrations than healthy controls. Serum and synovial fluid (SF) gremlin-1 concentrations increased according to advanced Kellgren-Lawrence grading stages. CONCLUSIONS Serum and SF gremlin-1 concentrations are correlated with the onset and severity of knee OA.

[Comparison of the effects of sciatic nerve block combined with continuted femoral nerve block or continuted adductor canal block on pain and motor function after total knee arthroplasty].

Objective: To compare the effect of sciatic nerve block (SNB) combined with continuted femoral nerve block (FNB) or continuted adductor canal block (ACB) on pain and motor function after total knee arthroplasty (TKA). Methods: A total of 60 patients with TKA-treated osteoarthritis of the knee who met the selection criteria were enrolled between November 2020 and February 2021 and randomised allocated into the study group (SNB combined with continuted ACB) and the control group (SNB combined with continuted FNB), with 30 cases in each group. There was no significant difference in gender, age, body mass, height, body mass index, preoperative Hospital for Special Surgery (HSS) score, femoral tibial angle, and medial proximal tibial angle between the two groups ( P>0.05). The operation time, the initial time to the ground, the initial walking distance, and the postoperative hospital stay were recorded. At 2, 4, 6, 12, 24, and 48 hours after operation, the numerical rating scale (NRS) score was used to evaluate the rest pain around the knee joint, the quadriceps femoris muscle strength was evaluated by the freehand muscle strength method, and the knee flexion and extension angles were measured. Results: There was no significant difference in the operation time and initial walking distance between the two groups ( P>0.05); the initial time to the ground and postoperative hospital stay of the study group were significantly shorter than those of the control group ( P<0.05). Except for the 48-hour postoperative NRS score of the study group, which was significantly lower than that of the control group ( P<0.05), there was no significant difference in the NRS scores between the two groups at the remaining time points ( P>0.05). The quadriceps femoris muscle strength from 4 to 24 hours postoperatively and the knee extension angle from 2 to 6 hours postoperatively of the study group were significantly better than those of the control group ( P<0.05); the differences in the quadriceps femoris muscle strength and knee extension and flexion angles between the two groups at the remaining time points were not significant ( P>0.05). Conclusion: SNB combined with either continuted ACB or continuted FNB can effectively relieve pain in patients after TKA, and compared with combined continuted FNB, combined continuted ACB has less effect on quadriceps femoris muscle strength, and patients have better recovery of knee flexion and extension mobility.

Impact of Prevention Strategies on Quality of Life in Patients with Osteoarthritis: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the impact of prevention strategies on the quality of life in patients with osteoarthritis (OA) through a comprehensive analysis of randomized controlled trials (RCTs). METHODS: A systematic search was conducted in multiple electronic databases, including Cochrane Library, PubMed, Embase, and ClinicalTrials.gov, up to June 10th, 2023. Eligible studies were RCTs assessing the effectiveness of prevention strategies in adult patients diagnosed with OA, with validated instruments used to measure quality of life outcomes. A total of 10 RCTs met the inclusion criteria and were included in the meta-analysis. The analyzed prevention strategies encompassed enhanced exercise, education, or a combination of both. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: The pooled results revealed a significant improvement in the quality of life of OA patients who underwent enhanced exercise or education compared to control groups (standardized mean difference = 0.44, 95% confidence interval 0.08-0.8). However, the overall quality of evidence was graded as low according to the Grading of Recommendations Assessment, Development and Evaluation assessment. CONCLUSIONS: This meta-analysis provides evidence that prevention strategies, particularly enhanced exercise or education, have a positive impact on the quality of life in patients with OA. Despite the observed benefits, the overall quality of evidence is limited, highlighting the need for larger, well-designed trials to strengthen the evidence base. These findings underscore the importance of implementing effective prevention strategies in the management of OA to improve patient outcomes and enhance their quality of life. Further research is warranted to optimize the selection and implementation of prevention strategies for OA patients.

Deguelin inhibits the proliferation of human multiple myeloma cells by inducing apoptosis and G2/M cell cycle arrest: Involvement of Akt and p38 MAPK signalling pathway.

Deguelin exhibits antiproliferative activity against various cancer cell types. Previous studies have reported that deguelin exhibits pro-apoptotic activity against human cancer cells. The current study aimed at further elaborating the anticancer effects of deguelin against multiple myeloma cells. Cell growth estimations were made through MTT assay. Phase contrast microscopy was used for the analysis of the viability of multiple myeloma cells. Colony formation from multiple myeloma cells was studied using a clonogenic assay. Antioxidative assays for determining levels of glutathione (GSH) and superoxide dismutase (SOD) were carried out after treating multiple myeloma cells with deguelin. The apoptosis of multiple myeloma cells was studied using AO/EB and Annexin V-FITC/PI staining methods. Multiple myeloma cell cycle analysis was performed through flow cytometry. mRNA expression levels were depicted using qRT-PCR. Migration and invasion of multiple myeloma cells were determined with the wound-healing and transwell assays, respectively. Deguelin specifically inhibited the multiple myeloma cell growth while the normal plasma cells were minimally affected. Multiple myeloma cells when treated with deguelin exhibited remarkably lower viability and colony-forming ability. Multiple myeloma cells treated with deguelin produced more SOD and had higher GSH levels. The multiple myeloma cell growth, migration, and invasion were significantly declined by in vitro administration of deguelin. In conclusion, deguelin treatment, when applied in vitro, induced apoptotic cell death and resulted in mitotic cessation at the G2/M phase through modulation of cell cycle regulatory mRNAs in multiple myeloma cells.

Characterization of PANoptosis-related genes with immunoregulatory features in osteoarthritis.

This study aimed to characterize PANoptosis-related genes with immunoregulatory features in osteoarthritis (OA) and investigate their potential diagnostic and therapeutic implications. Gene expression data from OA patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis and functional enrichment analysis were conducted to identify PANoptosis-related genes (PRGs) associated with OA pathogenesis. A diagnostic model was developed using LASSO regression, and the diagnostic value of key PRGs was evaluated using Receiver Operating Characteristic Curve (ROC) analysis. The infiltration of immune cells and potential small molecule agents were also examined. A total of 39 differentially expressed PANoptosis-related genes (DE-PRGs) were identified, with functional enrichment analysis revealing their involvement in inflammatory response regulation and immune modulation pathways. Seven key PRGs, including CDKN1A, EZH2, MEG3, NR4A1, PIK3R2, S100A8, and SYVN1, were selected for diagnostic model construction, demonstrating high predictive performance in both training and validation datasets. The correlation between key PRGs and immune cell infiltration was explored. Additionally, molecular docking analysis identified APHA-compound-8 as a potential therapeutic agent targeting key PRGs. This study identified and analyzed PRGs in OA, uncovering their roles in immune regulation. Seven key PRGs were used to construct a diagnostic model with high predictive performance. The identified PRGs' correlation with immune cell infiltration was elucidated, and APHA-compound-8 was highlighted as a potential therapeutic agent. These findings offer novel diagnostic markers and therapeutic targets for OA, warranting further in vivo validation and exploration of clinical applications.

Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative disease characterized by subchondral osteosclerosis, mainly due to osteoblast activity. This research investigates the function of Sik1, a member of the AMP-activated protein kinase family, in OA. Proteomic analysis was conducted on clinical samples from 30 OA patients, revealing a negative correlation between Sik1 expression and OA. In vitro experiments utilized BMSCs to examine the effect of Sik1 on osteogenic differentiation. BMSCs were cultured and induced toward osteogenesis with specific media. Sik1 overexpression was achieved through lentiviral transfection, followed by analysis of osteogenesis-associated proteins using Western blotting, RT-qPCR, and alkaline phosphate staining. In vivo experiments involved destabilizing the medial meniscus in mice to establish an OA model, assessing the therapeutic potential of Sik1. The CT scans and histological staining were used to analyze subchondral bone alterations and cartilage damage. The findings show that Sik1 downregulation correlates with advanced OA and heightened osteogenic differentiation in BMSCs. Sik1 overexpression inhibits osteogenesis-related markers in vitro and reduces cartilage damage and subchondral osteosclerosis in vivo. Mechanistically, Sik1 modulates osteogenesis and subchondral bone changes through Runx2 activity regulation. The research emphasizes Sik1 as a promising target for treating OA, suggesting its involvement in controlling bone formation and changes in the subchondral osteosclerosis.

Unveiling the role of RhoA and ferroptosis in vascular permeability: Implications for osteoarthritis.

Abnormal angiogenesis and increased vascular permeability of subchondral bone are key mechanisms related to osteoarthritis (OA). However, the precise mechanisms responsible for heightened vascular permeability in OA remain unclear. The present study used proteomics to identify protein expression in damaged subchondral bone compared with normal subchondral bone. The results suggest that Ras homolog family member A (RhoA) may be associated with the vascular permeability of subchondral bone and ferroptosis in OA. The results of analysis of clinical samples indicated a significant increase in expression of RhoA in the subchondral bone of OA. This were consistent with the proteomics findings. We found through western blotting, RT­PCR, and immunofluorescence that RhoA significantly increased the permeability of endothelial cells (ECs) by inhibiting inter­EC adhesion proteins (zona occludens­1, connexin 43 and Vascular endothelial­Cadherin) and actin filaments. Furthermore, RhoA induced ferroptosis core proteins (glutathione peroxidase 4,  solute carrier family 7 member 11 and acyl­CoA synthase long­chain family member 4, ACSL4) by influencing lipid peroxidation and mitochondrial function, leading to ferroptosis of ECs. This suggested an association between RhoA, ferroptosis and vascular permeability. Ferroptosis significantly increased permeability of ECs by inhibiting inter­EC adhesion proteins. RhoA increased vascular permeability by inducing ferroptosis of ECs. In vivo, inhibition of RhoA and ferroptosis significantly mitigated progression of OA by alleviating cartilage degeneration and subchondral bone remodeling in mice with destabilization of the medial meniscus. In conclusion, the present findings indicated that RhoA enhanced vascular permeability in OA by inducing ferroptosis. This may serve as a novel strategy for the early prevention and treatment of OA.