METTL14-mediated HOXA5 m6A modification alleviates osteoporosis via promoting WNK1 transcription to suppress NLRP3-dependent macrophage pyroptosis.

Background: Osteoporosis is a commonly diagnosed metabolic bone disease. NLRP3 inflammasome activation and pyroptosis are observed during osteoporosis. However, the mechanism by which NLRP3-mediated pyroptosis contributes to osteoporosis remains largely undefined. Methods: Ovariectomized (OVX) mice were employed as an in vivo model of osteoclastogenesis. H&E staining and micro-CT detected the histological changes and bone parameters in the femur tissues. RANKL-treated macrophages were used as the in vitro model of osteoclastogenesis, and LPS/ATP treatment was used as the macrophage pyroptosis model. The cytotoxicity, cytokine secretion and caspase-1 activity were assessed by LDH release assay, ELISA and flow cytometry, respectively. The osteoclast formation ability was detected by TRAP staining. qRT-PCR, IHC and Western blotting detected the expression and localization of METTL14, pyroptosis-related or osteoclast-specific molecules in femur tissues or macrophages. Mechanistically, MeRIP assessed the m6A modification of HOXA5. Luciferase and ChIP assays were employed to detect the direct association between HOXA5 and WNK1 promoter in macrophages. Results: METTL14, HOXA5 and WNK1 were decreased in OVX mice, which was associated with pyroptosis. METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis, along with the upregulation of WNK1. METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression, and HOXA5 regulated WNK1 expression via direct binding to its promoter. Functional studies showed that WNK1 knockdown counteracted METTL14- or HOXA5-suppressed pyroptosis and macrophage-osteoclast differentiation. In OVX mice, overexpression of METTL14 or HOXA5 alleviated osteoporosis via suppressing WNK1-dependent NLRP3 signaling. Conclusion: METTL14-mediated HOXA5 m6A modification increased its expression, thereby inducing WNK1 expression and suppressing NLRP3-dependent pyroptosis to alleviate osteoporosis. The combination of METTL14 or HOXA5 agonist with pyroptosis targeted therapy may be a promising therapeutic approach for osteoporosis. The Translational Potential of this Article·: •METTL14 or HOXA5 overexpression suppressed macrophage-osteoclast differentiation and pyroptosis in macrophages.·â€¢METTL14-mediated m6A modification stabilized HOXA5 mRNA and increased its expression.•HOXA5 regulated WNK1 expression via direct binding to its promoter.•Silencing of WNK1 reversed METTL14- or HOXA5-suppressed pyroptosis and macrophageosteoclast differentiation.·â€¢METTL14 or HOXA5 overexpression alleviated osteoporosis via suppressing WNK1-dependent NLRP3 signaling in OVX mice.

Selenium Nanoparticles Attenuate Cobalt Nanoparticle-Induced Skeletal Muscle Injury: A Study Based on Myoblasts and Zebrafish.

Cobalt alloys have numerous applications, especially as critical components in orthopedic biomedical implants. However, recent investigations have revealed potential hazards associated with the release of nanoparticles from cobalt-based implants during implantation. This can lead to their accumulation and migration within the body, resulting in adverse reactions such as organ toxicity. Despite being a primary interface for cobalt nanoparticle (CoNP) exposure, skeletal muscle lacks comprehensive long-term impact studies. This study evaluated whether selenium nanoparticles (SeNPs) could mitigate CoNP toxicity in muscle cells and zebrafish models. CoNPs dose-dependently reduced C2C12 viability while elevating reactive oxygen species (ROS) and apoptosis. However, low-dose SeNPs attenuated these adverse effects. CoNPs downregulated myogenic genes and α-smooth muscle actin (α-SMA) expression in C2C12 cells; this effect was attenuated by SeNP cotreatment. Zebrafish studies confirmed CoNP toxicity, as it decreased locomotor performance while inducing muscle injury, ROS generation, malformations, and mortality. However, SeNPs alleviated these detrimental effects. Overall, SeNPs mitigated CoNP-mediated cytotoxicity in muscle cells and tissue through antioxidative and antiapoptotic mechanisms. This suggests that SeNP-coated implants could be developed to eliminate cobalt nanoparticle toxicity and enhance the safety of metallic implants.

Osteosarcoma neutrophil extracellular trap network-associated gene recurrence and metastasis model.

Osteosarcoma (OS) is the most common malignancy in children and adolescents and has a high probability of recurrence and metastasis. A growing number of studies have shown that neutrophil extracellular traps (NETs) are strongly associated with cancer metastasis, but in osteosarcoma, genes associated with NETs that promote osteosarcoma recurrence and metastasis remain to be explored. We systematically investigated the gene expression patterns of NETs in OS samples from the GEO database. NETs molecular typing was evaluated based on NETs expression profiles, and the association between NETs molecular subtypes and immune microenvironment and metastatic features were explored. Ultimately, we constructed a signature model and column line graph associated with metastasis prediction and screened possible potential drugs for metastatic osteosarcoma. We established two different molecular subtypes of NETs, which showed significant differences in metastatic status, metastasis time, tumor immune microenvironment, and biological effects. We also constructed a NETs-related gene metastasis signature(NRGMS) to assess the expression pattern of NETs in patients to predict metastatic recurrence in osteosarcoma patients. We screened for TOMM40 and FH associated with metastatic recurrence in osteosarcoma patients. Overall, this study constructs a predictive model for osteosarcoma metastasis of NETs-related genes, which is expected to provide new insights into the metastasis of osteosarcoma.

Association between malnutrition and surgical site wound infection among spinal surgery patients: A meta-analysis.

A surgical site infection (SSI) is one of the most common complications of spinal surgery. Malnutrition has also been linked to SSI after other surgical procedures. However, whether malnutrition is a risk factor for SSI after spinal surgery remains controversial. Therefore, we performed a meta-analysis to comprehensively evaluate the relationship between malnutrition and SSI. Relevant studies of the correlation between malnutrition and SSI were retrieved from the Cochrane Library, EMBASE, PubMed, Web of Science, China National Knowledge Infrastructure and Wanfang Data from database inception to 21 May 2023. Two reviewers independently assessed the included studies, and a meta-analysis was performed using STATA 17.0 software. A total of 24 articles with 179 388 patients were included: 3919 and 175 469 cases comprised the SSI and control groups, respectively. The meta-analysis results showed that malnutrition significantly increased the SSI incidence (odds ratio, 1.811; 95% confidence interval, 1.512-2.111; p < 0.001). These results suggest that patients with malnutrition are at higher risk for SSI after surgery. However, because of significant differences in sample sizes among studies, and because some studies had limitations to their methodological quality, further validation of these results by additional high-quality studies with larger sample sizes is necessary.