Neutrophil extracellular traps induce the bone erosion of gout.

OBJECTIVE: To investigate the relationships between monosodium urate (MSU) crystals -induced neutrophil extracellular traps (NETs) and bone erosion in gout. METHODS: Animal models were used to study the relationship between NETs induced by MSU crystals and bone erosion. Neutrophils were treated with MSU crystals to induce NETs. The osteoblasts-like cells (OB) were then treated with NETs, and the supernatant was co-incubated with osteoclasts-like cells (OC). The NETs were digested with DNase, and the neutrophil elastase (NE) was inhibited with sivelestat sodium. Cell viability, mRNA, and protein expression were also assessed. RESULTS: After treating OB with NETs, the cell viability decreased. Yet, after digesting the DNA and inhibiting NE, the viability was moderately improved. The expression level of osteoprotegerin (OPG) and alkaline phosphatase (ALP) was up-regulated, while the expression level of receptor activator of nuclear factor kappa-B ligand (RANKL) was down-regulated in the sivelestat sodium + MSU group compared with MSU group. The number of OC was significantly elevated. In contrast, the number of OB was not increased in the tibia after establishing the gout model. The supernatant obtained from OB was treated with NETs promoting OC differentiation. The expression level of receptor activator of nuclear factor kappa-B (RANK), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (Cst K) was up-regulated in the MSU group compared with the normal control (NC) group. CONCLUSION: NETs induced by MSU crystals could inhibit osteoblasts viability and enhance the activity of osteoclasts.

Association between serum homocysteine and sarcopenia among hospitalized older Chinese adults: a cross-sectional study.

OBJECTIVE: Hyperhomocysteinemia (HHcy) is considered to increase the risk of sarcopenia (S) and remains controversial. In this study, we aimed to investigate the prevalence of S among older Chinese adults and explore whether homocysteine (Hcy) was independently associated with S. METHODS: This cross-sectional study was performed among older adults hospitalized in the Geriatric Hospital of Nanjing Medical University between June 2017 and December 2021. We measured all participants' serum Hcy levels, hand grip strength, gait speed and appendicular skeletal muscle index(ASMI) using bioelectrical impedance analysis (BIA). S was defined based on the criteria of the Asian Working Group for Sarcopenia 2 (AWGS2), which included muscle mass (ASMI< 7.0 kg/m2 for men and ASMI< 5.7 kg/m2 for women by BIA) and low muscle strength (handgrip strength < 28 kg for men and < 18 kg for women), and/or gait speed < 1.0 m/s. HHcy defined as Hcy ≥10 µmol/L. The strength of the association between Hcy and the risk of S was analyzed by multivariate logistic regression using three models that adjusted for possible confounding variables to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the 441 subjects, 161 (36.5%) were diagnosed with S, and 343 (77.8%) were diagnosed with HHcy. A significant association was detected between S and serum Hcy per 1-µmol/L increase after adjustment for age, gender, education, smoking, body mass index (BMI), Mini Nutritional Assessment Short Form (MNA-SF), alanine aminotransferase (ALT), C-reactive protein (CRP), hemoglobin (Hb), albumin (ALB), diabetes, kidney disease, and statin use (OR = 1.07, 95% CI = 1.03-1.12, P = 0.002). The OR for S in the HHcy group (≥10 µmol/L) was nearly 5-fold that in the normal Hcy group (OR 4.96, 95% CI 2.67-9.24, P < 0.001). In a gender-based subgroup analysis that adjusted for age, education, smoking, BMI, MNA-SF, ALT, CRP, Hb, and ALB, female subjects with HHcy had an increased risk of S (OR 10.35, 95% CI 2.84-37.68, P < 0.001). CONCLUSIONS: Our results demonstrated that elevated Hcy levels have an independent association with S in older adults. This suggests that the downward adjustment of HHcy (cutoff value < 10 µmol/l) might decrease the risk of S.

The effects of aerobic exercise on body composition in overweight and obese patients with gout: a randomized, open-labeled, controlled trial.

BACKGROUND: Overweight and obesity are typical risk factors for the increased prevalence and incidence of gout. The existing guidelines unequivocally indicated that exercise is highly advantageous for patients with gout. Nevertheless, there is still a lack of specific guidance and clinical evidence. The effects of exercise on improving gout, and the optimal frequency, timing, and types of exercise have not been fully clarified. The present trial aims to determine the effects of a specific aerobic exercise program on body composition in overweight and obese patients with gout. METHODS: In this randomized, open-labeled, controlled trial, a total of 60 overweight and obese patients with gout [body mass index (BMI) ≥ 24 kg/m2; age,18-55 years old] are equally randomized (1:1) into two groups (n = 30): moderate-intensity aerobic exercise group (MIAEG), heart rate reserve (HRR) = [(HRmax-HRrest) × 60% intensity] + HRrest, and control group (CG). The moderate-intensity aerobic exercise training program will be conducted for 30-40 min/session and 3 days/week for 12 weeks. Participants in the CG will be asked to avoid making changes in their exercise habits. There will be no limitation in the type of exercise. The primary outcome is the number of patients whose body fat is reduced after 12 weeks. The secondary outcomes include the changes in BMI, waist-to-hip ratio (WHR), insulin resistance index (IRI), serum uric acid (sUA), serum creatinine (SCr), estimated glomerular filtration rate (eGFR), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hepatic steatosis, and adverse effects after 12 weeks. One-way analysis of variance (ANOVA) will be used to compare the mean values of normally distributed variables between MIAEG and GC. DISCUSSION: The effect and optimal frequency of exercise for improving the status of overweight and obese patients with gout have not yet been determined. We design a 12-week randomized controlled trial and evaluate the effects of individualized aerobic exercise program on patients with gout. The results may assist such patients with a personalized scientific exercise program based on the disease status and motor abilities, so that patients are prone to exercise under the condition of low risk and achieve the greatest benefits. TRIAL REGISTRATION: ChiCTR2200062153. Registered on July 25, 2022, with ChiCTR. http://www.chictr.org.cn/.

The Inhibition of Osteoblast Viability by Monosodium Urate Crystal-Stimulated Neutrophil-Derived Exosomes.

Background and Objective: Bone erosion is common in patients with gout. The role of neutrophil-derived exosomes in gouty bone erosion remains elusive. This study aimed to investigate the functions of the neutrophil-derived exosomes in the development of bone erosion in gout. Methods: Neutrophil-derived exosomes were collected and assessed by transmission electron microscopy and nanoparticle tracking analysis. Cell counting kit-8 assay was applied to evaluate cell viability, and cell apoptosis was assessed by flow cytometry. In addition, quantitative Real-time PCR and Western blotting were used to determine the expression levels of alkaline phosphatase (ALP), osteoprotegerin (OPG), and receptor activator of nuclear factor-κB ligand (RANKL). Neutrophil-derived exosomes were tagged with PKH67. The miRNA expression profiles of exosomes and human fetal osteoblasts (hFOB) were compared using high-throughput sequencing. Functional miRNAs transfected into hFOB after co-incubation with exosomes were selected and validated by preliminary qPCR. Results: Neutrophil-derived exosomes were stimulated by monosodium urate (MSU). The exosomes could inhibit the viability of the hFOB, and the expression levels of ALP and OPG were down-regulated, while the expression level of RANKL was up-regulated. However, there was no significant difference in the viability of osteoclasts and the expression of nuclear factor of activated T cells 1. Exosomes were observed in the cytoplasm under a confocal microscopy, confirming that exosomes could be taken up by hFOB. In total, 2590 miRNAs were found, of which 47 miRNAs were differentially expressed. Among the delivered miRNAs, miR-1246 exhibited the highest level of differential expression. The viability of hFOB was reduced by miR-1246 mimics and increased by miR-1246 inhibitors. There was no significant difference in hFOB apoptosis rate between the miR-1246 mimic and miR-1246 inhibitor group. MiR-1246 overexpression decreased the expression levels of ALP and OPG, whereas increasing the expression level of RANKL. In contrast, miR-1246 inhibitor increased the expression levels of ALP and OPG, while decreasing the expression level of RANKL. Neutrophil-derived exosomes stimulated by MSU could increase the expression of miR-1246. Conclusion: Neutrophil-derived exosomes stimulated by MSU could inhibit the viability of osteoblasts.

Zhengqing fengtongning sustained-release tablets prevents gout flares in the process of ULT: A randomized, positive control, double-blind, double-simulation, multicenter trial.

INTRODUCTION: When initiating urate-lowering therapy, using anti-inflammatory prophylaxis therapy for at least 3 to 6 months is strongly recommended. Previous studies have found that zhengqing fengtongning sustained-release tablets (sinomenine) can improve inflammation in the acute phase of gout; however, the efficacy of urate-lowering therapy in reducing frequency of acute flares still needs to be investigated. The aim of the present study is to explore the efficacy and safety of sinomenine for prophylaxis of acute flares when initiating urate-lowering therapy. METHODS AND ANALYSIS: This randomized, placebo-controlled, double-blinded trial will include a total of 210 gout patients who meet the study criteria. The patients will be randomized (1:1) to the test group and the control group. The intervention is planned to be performed for 12 weeks with a follow-up of 12 weeks. All patients would be administered febuxostat (40 mg/d) and concomitant anti-inflammatory prophylaxis therapy. Sinomenine and colchicine placebo are administered in the sinomenine group, sinomenine placebo and colchicine are administered in the colchicine group. The primary outcome is the rate of acute gout flares in subjects within 12 weeks of the treatment period. The secondary outcomes include the times of acute gout flares and the duration of each acute flares within 12 weeks; the compliance rate in patients whose UA levels ≤6.0 mg/dL (360 µmol/L) at the weekend of 2nd, 4th, 8th, and 12th week in each group; the proportion of patients with ≥1 and ≥2 gout flares within 12 weeks; average visual analogue scale/score pain score during gout flares; and the oral dose of etoricoxib will be used to control the onset of acute flares within 12 weeks. ETHICS AND DISSEMINATION: The Institutional Medical Ethics Committee have approved the trial protocol. We plan to publish the results of this study in a peer-reviewed journal. TRIAL REGISTRATION: ChiCTR, ChiCTR2100045114, Registered 8 April 2021 http://www.chictr.org.cn/showproj.aspx?proj=124688.

Effect of alkalized urine on renal calculi in patients with gout: a protocol for a placebo-controlled, double-blinded randomized controlled trial.

BACKGROUND: The prevalence of renal calculi in patients with gout is high. Alkalized urine has been recommended by the 2020 European Association of Urology (EAU) guidelines to promote calculus dissolution. However, randomized controlled trials are lacking. METHODS: In the protocol of this randomized, placebo-controlled, double-blinded trial, patients with gout combined with renal calculi are randomized (1:1) to the placebo and sodium bicarbonate groups. The intervention would be performed for 24 weeks, the 1-12 weeks are double-blinded, and the 13-24 weeks are open-labeled. Sodium bicarbonate (1 g tid) will be performed for 24 weeks in the sodium bicarbonate group. The placebo will be performed for 12 weeks and not be performed from 13 weeks to 24 weeks in the placebo group. All subjects will be administered febuxostat (40 mg/day) for 24 weeks and receive concomitant anti-inflammatory prophylaxis therapy for 12 weeks. The primary outcome is the proportion of patients whose renal calculus volume will be reduced after 12 weeks of treatment. The secondary outcomes include the volume changes of renal calculi, uric acid changes, the proportion of patients with serum uric acid (sUA) levels < 360 µmol/L, the changes in estimated glomerular filtration rate (eGFR), the pH value of urine, and the incidence of adverse events after treatment for 12 and 24 weeks. DISCUSSION: This study will evaluate the efficacy and safety of sodium bicarbonate-alkalized urine on renal calculi in patients with gout. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2100045183. Registered on April 7, 2021, with ChiCTR.