Causal relationship between circulating inflammatory factors and osteoporosis: a bidirectional Mendelian randomization study.

OBJECTIVE: Osteoporosis (OP), a persistent metabolic bone disorder linked with inflammation, has an undetermined cause. In our research, we employed bidirectional Mendelian randomization (MR) to investigate the interplay between OP and inflammation agents. MATERIALS AND METHODS: We performed two-way pooled-level MR analyses to characterize the causal relationship between 41 circulating inflammatory modulators and OP. Genetic variation data for the 41 regulatory factors associated with inflammation were obtained from genome-wide association studies (GWASs) of human cytokines. Bone mineral density (BMD) was utilized as a phenotype for OP in our approach. The BMD dataset, sourced from the GEFOS consortium, a large GWAS meta-analysis study and UK Biobank, was classified based on varied sections [whole body (TB), lumbar spine (LS), femoral neck (FN), forearm (FA), and heel] and age brackets (0-15 years, 15-30 years, 30-45 years, 45-60 years, and above 60 years). Primary MR analyses were executed using the inverse variance weighting (IVW) method, and sensitivity analyses were performed using the MR-Egger, weighted median, simple model, and weighted model. Cochran's Q test was utilized to evaluate the existence of heterogeneity. We used MR-Egger regression and MR multiplicity of residuals and outliers (MR-PRESSO) to assess pleiotropy. RESULTS: After false discovery rate (FDR) correction, elevated levels of circulating interleukin-8 (IL-8) [ß = 0.072 (0.031-0.114), p < 0.01], macrophage inflammatory protein-1b (MIP-1ß) [ß = 0.008 (0.003-0.013), p < 0.01; ß = 0.026 (0.009-0.042), p < 0.01], and cutaneous T-cell attracting chemokine (CTACK) [ß = 0.037 (0.017-0.056), p < 0.01] was associated with a reduced risk of OP. Reduced levels of hepatocyte growth factor (HGF), IL-1ra, IL-10, macrophage colony-stimulating factor (MCSF), and MIP-1α were associated with a reduced risk of OP [ß = -0.030 (-0.047 - -0.013), p < 0.01; ß = -0.025 (-0.041 - -0.010), p < 0.01; ß = -0.018 (-0.029 - -0.007), p < 0.01; ß = -0.060 (-0.097 - -0.024), p < 0.01; ß = -0.118 (-0.190 - -0.047), p < 0.01]. We observed a significant causal correlation between FN-BMD and MCP-3 (FDR < 0.05). The occurrence of OP may also lead to elevated levels of MCP3 [ß = -0.466 (-0.714 - -0.217), p < 0.01]. The reliability of the results was confirmed by sensitivity analyses. CONCLUSIONS: This study demonstrated the pathogenic role of circulating inflammatory modulators in OP using bidirectional MR analysis. This further deepens the understanding of OP pathogenesis and provides new ideas for therapeutic intervention in OP.

Development and experimental validation of an energy metabolism-related gene signature for diagnosing of osteoporosis.

Osteoporosis is usually caused by excessive bone resorption and energy metabolism plays a critical role in the development of osteoporosis. However, little is known about the role of energy metabolism-related genes in osteoporosis. This study aimed to explore the important energy metabolism-related genes involved in the development of osteoporosis and develop a diagnosis signature for osteoporosis. The GSE56814, GSE62402, and GSE7158 datasets were downloaded from the NCBI Gene Expression Omnibus. The intersection of differentially expressed genes between high and low levels of body mineral density (BMD) and genes related to energy metabolism were screened as differentially expressed energy metabolism genes (DE-EMGs). Subsequently, a DE-EMG-based diagnostic model was constructed and differential expression of genes in the model was validated by RT-qPCR. Furthermore, a receiver operating characteristic curve and nomogram model were constructed to evaluate the predictive ability of the diagnostic model. Finally, the immune cell types in the merged samples and networks associated with the selected optimal DE-EMGs were constructed. A total of 72 overlapped genes were selected as DE-EMGs, and a five DE-EMG based diagnostic model consisting B4GALT4, ADH4, ACAD11, B4GALT2, and PPP1R3C was established. The areas under the curve of the five genes in the merged training dataset and B4GALT2 in the validation dataset were 0.784 and 0.790, respectively. Moreover, good prognostic prediction ability was observed using the nomogram model (C index = 0.9201; P = 5.507e-14). Significant differences were observed in five immune cell types between the high- and low-BMD groups. These included central memory, effector memory, and activated CD8 T cells, as well as regulatory T cells and activated B cells. A network related to DE-EMGs was constructed, including hsa-miR-23b-3p, DANCR, 17 small-molecule drugs, and two Kyoto Encyclopedia of Genes and Genomes pathways, including metabolic pathways and pyruvate metabolism. Our findings highlighted the important roles of DE-EMGs in the development of osteoporosis. Furthermore, the DANCR/hsa-miR-23b-3p/B4GALT4 axis might provide novel molecular insights into the process of osteoporosis development.

SIRT1 and ZNF350 as novel biomarkers for osteoporosis: a bioinformatics analysis and experimental validation.

BACKGROUND: Osteoporosis (OP) is characterized by bone mass decrease and bone tissue microarchitectural deterioration in bone tissue. This study identified potential biomarkers for early diagnosis of OP and elucidated the mechanism of OP. METHODS: Gene expression profiles were downloaded from Gene Expression Omnibus (GEO) for the GSE56814 dataset. A gene co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to identify key modules associated with healthy and OP samples. Functional enrichment analysis was conducted using the R clusterProfiler package for modules to construct the transcriptional regulatory factor networks. We used the "ggpubr" package in R to screen for differentially expressed genes between the two samples. Gene set variation analysis (GSVA) was employed to further validate hub gene expression levels between normal and OP samples using RT-PCR and immunofluorescence to evaluate the potential biological changes in various samples. RESULTS: There was a distinction between the normal and OP conditions based on the preserved significant module. A total of 100 genes with the highest MM scores were considered key genes. Functional enrichment analysis suggested that the top 10 biological processes, cellular component and molecular functions were enriched. The Toll-like receptor signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, osteoclast differentiation, JAK-STAT signaling pathway, and chemokine signaling pathway were identified by Kyoto Encyclopedia of Genes and Genomes pathway analysis. SIRT1 and ZNF350 were identified by Wilcoxon algorithm as hub differentially expressed transcriptional regulatory factors that promote OP progression by affecting oxidative phosphorylation, apoptosis, PI3K-Akt-mTOR signaling, and p53 pathway. According to RT-PCR and immunostaining results, SIRT1 and ZNF350 levels were significantly higher in OP samples than in normal samples. CONCLUSION: SIRT1 and ZNF350 are important transcriptional regulatory factors for the pathogenesis of OP and may be novel biomarkers for OP treatment.

GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease.

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.

Periodontitis and osteoporosis: a two-sample Mendelian randomization analysis.

The incidences of periodontitis and osteoporosis are rising worldwide. Observational studies have shown that periodontitis is associated with increased risk of osteoporosis. We performed a Mendelian randomization (MR) study to genetically investigate the causality of periodontitis on osteoporosis. We explored the causal effect of periodontitis on osteoporosis by MR analysis. A total of 9 single nucleotide polymorphisms (SNP) were related to periodontitis. The primary approach in this MR analysis was the inverse variance-weighted (IVW) method. Simple median, weighted median, and penalized weighted median were used to analyze sensitivity. The fixed-effect IVW model and random-effect IVW model showed no significant causal effect of genetically predicted periodontitis on the risk of osteoporosis (OR=1.032; 95%CI: 0.923-1.153; P=0.574; OR=1.032; 95%CI: 0.920-1.158; P=0.588, respectively). Similar results were observed in simple mode (OR=1.031; 95%CI: 0.780-1.361, P=0.835), weighted mode (OR=1.120; 95%CI: 0.944-1.328, P=0.229), simple median (OR=1.003; 95%CI: 0.839-1.197, P=0.977), weighted median (OR=1.078; 95%CI: 0.921-1.262, P=0.346), penalized weight median (OR 1.078; 95%CI: 0.919-1.264, P=0.351), and MR-Egger method (OR=1.360; 95%CI: 0.998-1.853, P=0.092). There was no heterogeneity in the IVW and MR-Egger analyses (Q=7.454, P=0.489 and Q=3.901, P=0.791, respectively). MR-Egger regression revealed no evidence of a pleiotropic influence through genetic variants (intercept: -0.004; P=0.101). The leave-one-out sensitivity analysis indicated no driven influence of any individual SNP on the association between periodontitis and osteoporosis. The Mendelian randomization analysis did not show a significant detrimental effect of periodontitis on the risk of osteoporosis.

Potential causal association between leisure sedentary behaviors and osteoporosis: A two-sample Mendelian randomization analysis.

Previous observational studies have observed a correlation between sedentary behavior and osteoporosis. However, conclusions from these studies have been contradictory. To explore the potential causal relationship between sedentary behavior and osteoporosis, we conducted a Mendelian randomization analysis. A two-sample Mendelian randomization was adopted to explore the causal relationship of leisure sedentary behavior with osteoporosis. We employed 5 methods to estimate the causal associations between leisure sedentary behavior and osteoporosis. Univariable Mendelian randomization results provided evidence for the causal relationship of the time spent on computer-use with the bone mineral density estimated by heel quantitative ultrasound (eBMD) (inverse variance weighted [IVW]: ß (95% confidence interval [CI]) - 0.150 (-0.270 to -0.031), P = .013; weighted median: ß (95%CI) - 0.195 (-0.336 to -0.055), P = .006). Similar associations were observed in the driving forearm bone mineral density (FABMD) (IVW: ß (95%CI) - 0.933 (-1.860 to -0.007), P = .048) and driving lumbar spine bone mineral density (IVW: ß (95%CI) - 0.649 (-1.175 to -0.124), P = .015). However, we did not find a significant causal relationship between the time spent on watching TV and bone mineral density. Research showed that there was a causal relationship between the time spent on computer use and driving time and eBMD, FABMD, and lumbar spine bone mineral density.

Complex interplay of neurodevelopmental disorders (NDDs), fractures, and osteoporosis: a mendelian randomization study.

BACKGROUND: Neurodevelopmental disorders (NDDs), such as Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), and Tourette Syndrome (TS), have been extensively studied for their multifaceted impacts on social and emotional well-being. Recently, there has been growing interest in their potential relationship with fracture risks in adulthood. This study aims to explore the associations between these disorders and fracture rates, in order to facilitate better prevention and treatment. METHODS: Employing a novel approach, this study utilized Mendelian randomization (MR) analysis to investigate the complex interplay between ADHD, ASD, TS, and fractures. The MR framework, leveraging extensive genomic datasets, facilitated a systematic examination of potential causal relationships and genetic predispositions. RESULTS: The findings unveil intriguing bidirectional causal links between ADHD, ASD, and specific types of fractures. Notably, ADHD is identified as a risk factor for fractures, with pronounced associations in various anatomical regions, including the skull, trunk, and lower limbs. Conversely, individuals with specific fractures, notably those affecting the femur and lumbar spine, exhibit an increased genetic predisposition to ADHD and ASD. In this research, no correlation was found between TS and fractures, or osteoporosis.These results provide a genetic perspective on the complex relationships between NDDs and fractures, emphasizing the importance of early diagnosis, intervention, and a holistic approach to healthcare. CONCLUSION: This research sheds new light on the intricate connections between NDDs and fractures, offering valuable insights into potential risk factors and causal links. The bidirectional causal relationships between ADHD, ASD, and specific fractures highlight the need for comprehensive clinical approaches that consider both NDDs and physical well-being.

Association between alcohol intake and bone mineral density: results from the NHANES 2005-2020 and two-sample Mendelian randomization.

We used the data from the NHANES cross-sectional study among 14,113 participants and indicated a positive correlation between alcohol intake frequency and bone mineral density in different body sites. Mendelian randomization was conducted, and no causal relationship is significant between these two variables. The study can provide some suggestions on the daily consumption of alcohol for osteoporosis patients. PURPOSE: The effect of alcohol intake on bone mineral density (BMD) remains unclear. This study explored the association and causality between alcohol intake and BMD. METHODS: Based on the 2005-2020 National Health and Nutrition Examination Survey including 14,113 participants, we conducted co-variate-adjusted multilinear regression analyses to explore the association between alcohol intake levels and spine or femur BMD. To evaluate the causal association between alcohol intake frequency and bone mineral density, the inverse variance weighted approach of two-sample Mendelian randomization (MR) was used with genetic data from the Medical Research Council Integrative Epidemiology Unit (462,346 cases) for alcohol intake frequency and the Genetic Factors for Osteoporosis Consortium (28,496 cases) for lumbar spine and femur neck BMD (32,735 cases). RESULTS: Compared with non-drinkers, total femur BMDs but not total spine BMD increased with daily alcohol intake in males (ß = 3.63*10-2 for mild drinkers, ß = 4.21*10-2 for moderate drinkers, and ß = 4.26*10-2 for heavy drinkers). By contrast, the higher total spine BMD in females was related to higher alcohol intake levels (ß = 2.15*10-2 for mild drinkers, ß = 2.59*10-2 for moderate drinkers, and ß = 3.88*10-2 for heavy drinkers). Regarding the two-sample MR results, no causal relationship was observed between alcohol intake frequency and lumbar spine BMD (odds ratio [OR] = 1.016, P = 0.789) or femur neck BMD (OR = 1.048, P = 0.333). CONCLUSION: This study suggests a positive association between alcohol intake frequency and BMD, although the causal relationship was not significant.

Associations of residential greenness with bone mineral density and osteoporosis: the modifying effect of genetic susceptibility.

OBJECTIVES: To investigate the associations of residential greenness with bone mineral density and incident osteoporosis, and further evaluate the potential modifying effect of genetic susceptibility. METHODS: We used the Normalised Difference Vegetation Index (NDVI) at various buffer distances, including 300 m (NDVI300m), 500 m (NDVI500m), 1000 m (NDVI1000m) and 1500 m (NDVI1500m), to serve as indicators of greenness. We fitted linear regression, logistic regression and Cox proportional hazard models to assess the associations of residential greenness with estimated bone mineral density (eBMD), prevalent osteoporosis and incident osteoporosis, respectively. With the Polygenic Risk Score (PRS) for osteoporosis, we further assessed the joint effects of genetic risk and greenness on the risk of osteoporosis. We conducted causal mediation analyses to explore potential mediators. RESULTS: Each IQR increase in NDVI300m was associated with 0.0007 (95% CI 0.0002 to 0.0013) increase in eBMD, 6% lower risk of prevalent osteoporosis (OR 0.94; 95% CI 0.92 to 0.97) and 5% lower risk of incident osteoporosis (HR 0.95; 95% CI 0.93 to 0.98). The joint effects of greenness and PRS on the risk of osteoporosis displayed a clear dose-response pattern. Compared with individuals exposed to low NDVI levels and high genetic risk, those exposed to high NDVI levels and low genetic risk had a 56% (95% CI 51% to 61%) lower risk of osteoporosis. The primary mediators in the association between greenness and incident osteoporosis were identified as PM2.5 and NO2. CONCLUSIONS: Residential greenness was associated with higher bone mineral density and decreased risk of incident osteoporosis.

Knockdown of the UL-16 binding protein 1 promotes osteoblast differentiation of human mesenchymal stem cells by activating the SMAD2/3 pathway.

Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts. The regulatory mechanisms of differentially expressed genes (DEGs) in pathogenesis of osteoporosis are of significant and needed to be further investigated. GSE100609 dataset downloaded from Gene Expression Omnibus (GEO) database was used to identified DEGs in osteoporosis patients. KEGG analysis was conducted to demonstrate signaling pathways related to enriched genes. Osteoporosis patients and the human mesenchymal stem cells (hMSCs) were obtained for in vivo and in vitro resaerch. Lentivirus construction and viral infection was used to knockdown genes. mRNA expression and protein expression were detected via qRT-PCR and western blot assay separately. Alkaline phosphatase (ALP) activity detection, alizarin Red S (ARS) staining, and expression of bone morphogenetic protein 2 (BMP2), osteocalcin (OCN) and Osterix were evaluated to determine osteoblast differentiation capacity. UL-16 binding protein 1 (ULBP1) gene was upregulated in osteoporosis and downregulated in differentiated hMSCs. Knockdown of ULBP1 increased ALP activity, mineralization ability evaluated by ARS staining, expression of BMP2, OCN and Osterix in differentiated hMSCs. Furthermore, rescue experiment demonstrated that suppressed ULBP1 boosted osteoblast differentiation by activating TNF-ß signaling pathway. Knockdown of ULBP1 gene could promoted osteoblast differentiation by activating TNF-ß signaling pathway in differentiated hMSCs. ULBP1 may be a the Achilles' heel of osteoporosis, and suppression of ULBP1 could be a promising treatment for osteoporosis.

mir-150-5p inhibits the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by targeting irisin to regulate the p38/MAPK signaling pathway.

PURPOSE: To study the effect of miR-150-5p on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), and further explore the relationship between its regulatory mechanism and irisin. METHODS: We isolated mouse BMSCs, and induced osteogenic differentiation by osteogenic induction medium. Using qPCR to detect the expression of osteogenic differentiation-related genes, western blot to detect the expression of osteogenic differentiation-related proteins, and luciferase reporter system to verify that FNDC5 is the target of miR-150-5p. Irisin intraperitoneal injection to treat osteoporosis in mice constructed by subcutaneous injection of dexamethasone. RESULTS: Up-regulation of miR-150-5p inhibited the proliferation of BMSCs, and decreased the content of osteocalcin, ALP activity, calcium deposition, the expression of osteogenic differentiation genes (Runx2, OSX, OCN, OPN, ALP and BMP2) and protein (BMP2, OCN, and Runx2). And down-regulation of miR-150-5p plays the opposite role of up-regulation of miR-150-5p on osteogenic differentiation of BMSCs. Results of luciferase reporter gene assay showed that FNDC5 gene was the target gene of miR-150-5p, and miR-150-5p inhibited the expression of FNDC5 in mouse BMSCs. The expression of osteogenic differentiation genes and protein, the content of osteocalcin, ALP activity and calcium deposition in BMSCs co-overexpressed by miR-150-5p and FNDC5 was significantly higher than that of miR-150-5p overexpressed alone. In addition, the overexpression of FNDC5 reversed the blocked of p38/MAPK pathway by the overexpression of miR-150-5p in BMSCs. Irisin, a protein encoded by FNDC5 gene, improved symptoms in osteoporosis mice through intraperitoneal injection, while the inhibitor of p38/MAPK pathway weakened this function of irisin. CONCLUSION: miR-150-5p inhibits the osteogenic differentiation of BMSCs by targeting irisin to regulate the/p38/MAPK signaling pathway, and miR-150-5p/irisin/p38 pathway is a potential target for treating osteoporosis.

Enhancing 3D DNA Walker-Induced CRISPR/Cas12a Technology for Highly Sensitive Detection of ExomicroRNA Associated with Osteoporosis.

Exosomal microRNAs (exomiRNAs) have emerged as promising biomarkers for the early clinical diagnosis of osteoporosis. However, their limited abundance and short length in peripheral blood present significant challenges for the accurate detection of exomiRNAs. Herein, we have designed and implemented an efficacious fluorescence-based biosensor for the highly sensitive detection of exomiRNA associated with osteoporosis, leveraging the enhancing 3D DNA walker-induced CRISPR/Cas12a technology. The engineered DNA walker is capable of efficiently transforming target exomiRNA into amplifying DNA strands, thereby enhancing the sensitivity of the developed biosensor. Concurrently, the liberated DNA strands serve as activators to trigger Cas12a trans-cleavage activity, culminating in a significantly amplified fluorescent signal for the highly sensitive detection of exomiRNA-214. Under optimal conditions, the devised technology demonstrated the capacity to detect target exomiRNA-214 at concentrations as low as 20.42 fM, encompassing a wide linear range extending from 50.0 fM to 10.0 nM. Moreover, the fluorescence-based biosensor could accurately differentiate between healthy individuals and osteoporosis patients via the detection of exomiRNA-214, which was in agreement with RT-qPCR results. As such, this biosensing technology offers promise as a valuable tool for the early diagnosis of osteoporosis.

Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis.

MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1. Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast-specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Notably, single-cell transcriptome analysis of clinical bone samples reveals that reduced MALAT1 expression in pre-osteoclasts and osteoclasts is associated with osteoporosis and metastatic bone lesions. Altogether, these findings identify Malat1 as a lncRNA that protects against osteoporosis and bone metastasis.

Causal effect of education on bone mineral density: A Mendelian randomization study.

Education level may have some association with the incidence of osteoporosis, but it is elusive if this association is causal. This two-sample Mendelian randomization analysis focused on the causal effect of education level on femoral neck bone mineral density (FN-BMD), forearm BMD, lumbar spine BMD, and heel BMD. Twelve single nucleotide polymorphisms were used as instrumental variables. The results suggested that high education level was associated with improved FN-BMD (beta-estimate: 0.406, 95% confidence interval: 0.061 to 0.751, standard error: 0.176, P-value = .021). There were null association between education and other sites of bone mineral density. Our results found the causal effect of high education level on improved FN-BMD, and improved educational attainment may be beneficial to prevent osteoporosis.

Mg-ZIF nanozyme regulates the switch between osteogenic and lipogenic differentiation in BMSCs via lipid metabolism.

The accumulation of reactive oxygen species (ROS) within the bone marrow microenvironment leads to diminished osteogenic differentiation and heightened lipogenic differentiation of mesenchymal stem cells residing in the bone marrow, ultimately playing a role in the development of osteoporosis (OP). Mitigating ROS levels is a promising approach to counteracting OP. In this study, a nanozyme composed of magnesium-based zeolitic imidazolate frameworks (Mg-ZIF) was engineered to effectively scavenge ROS and alleviate OP. The results of this study indicate that Mg-ZIF exhibits significant potential in scavenging ROS and effectively promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs). Additionally, Mg-ZIF was found to inhibit the differentiation of BMSCs into adipose cells. In vivo experiments further confirmed the ability of Mg-ZIF to mitigate OP by reducing ROS levels. Mechanistically, Mg-ZIF enhances the differentiation of BMSCs into osteoblasts by upregulating lipid metabolic pathways through ROS scavenging. The results indicate that Mg-ZIF has potential as an effective therapeutic approach for the treatment of osteoporosis.

Integration analysis of lncRNA and mRNA expression data identifies DOCK4 as a potential biomarker for elderly osteoporosis.

BACKGROUND: We aimed to identify some potential biomarkers for elderly osteoporosis (OP) by integral analysis of lncRNA and mRNA expression data. METHODS: A total of 8 OP cases and 5 healthy participants were included in the study. Fasting peripheral venous blood samples were collected from individuals, and total RNA was extracted. RNA-seq library was prepared and sequenced on the Illumina HiSeq platform. Differential gene expression analysis was performed using "DESeq2" package in R language. Functional enrichment analysis was conducted using the "clusterProfiler" package, and the cis- and trans-regulatory relationships between lncRNA and target mRNA were analyzed by the lncTar software. A protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified through the MCODE plugin in Cytoscape. RESULTS: We identified 897 differentially expressed lncRNAs (DELs) and 1366 differentially expressed genes (DEGs) between normal and OP samples. After co-expression network analysis and cis-trans regulatory genes analysis, we identified 69 candidate genes regulated by lncRNAs. Then we further screened 7 genes after PPI analysis. The target gene DOCK4, trans-regulated by two lncRNAs, was found to be significantly upregulated in OP samples. Additionally, 4 miRNAs were identified as potential regulators of DOCK4. The potential diagnostic value of DOCK4 and its two trans-regulatory lncRNAs was supported by ROC analysis, indicating their potential as biomarkers for OP. CONCLUSION: DOCK4 is a potential biomarker for elderly osteoporosis diagnostic. It is identified to be regulated by two lncRNAs and four miRNAs.

Exploring epigenetic strategies for the treatment of osteoporosis.

The worldwide trend toward an aging population has resulted in a higher incidence of chronic conditions, such as osteoporosis. Osteoporosis, a prevalent skeletal disorder characterized by decreased bone mass and increased fracture risk, encompasses primary and secondary forms, each with distinct etiologies. Mechanistically, osteoporosis involves an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Current pharmacological interventions for osteoporosis, such as bisphosphonates, denosumab, and teriparatide, aim to modulate bone turnover and preserve bone density. Hormone replacement therapy and lifestyle modifications are also recommended to manage the condition. While current medications offer therapeutic options, they are not devoid of limitations. Recent studies have highlighted the importance of epigenetic mechanisms, including DNA methylation and histone modifications, in regulating gene expression during bone remodeling. The use of epigenetic drugs, or epidrugs, to target these mechanisms offers a promising avenue for therapeutic intervention in osteoporosis. In this review, we comprehensively examine the recent advancements in the application of epidrugs for treating osteoporosis.

[Progress in Gene Polymorphisms Associated With Osteoporosis Susceptibility in Zhuang Ethnic Group in Guangxi].

The purpose of this paper is to systematically summarize the gene polymorphisms associated with osteoporosis(OP)susceptibility in Zhuang ethnic group in Guangxi.These genes mainly encode vitamin D receptor,estrogen receptor,calcitonin receptor,and adiponectin.The genotype and allele distribution frequency were compared between Zhuang ethnic group and other ethnic groups,which can clarify the existing genes and the potential gene polymorphism associated with OP in Zhuang ethnic group.The findings provide a representative solution for the subsequent research on the genes associated with OP susceptibility in ethnic minorities.

Corynoline Suppresses Osteoclastogenesis and Attenuates ROS Activities by Regulating NF-κB/MAPKs and Nrf2 Signaling Pathways.

Declining estrogen production in postmenopausal females causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. Although clinical drugs are currently available for the treatment of osteoporosis, sustained medication use is accompanied by serious side effects. Corydalis bungeana Herba, a famous traditional Chinese herb listed in the Chinese Pharmacopoeia Commission, constitutes various traditional Chinese Medicine prescriptions, which date back to thousands of years. One of the primary active components of C. bungeana Turcz. is Corynoline (Cor), a plant isoquinoline alkaloid derived from the Corydalis species, which possesses bone metabolism disease therapeutic potential. The study aimed at exploring the effects as well as mechanisms of Cor on osteoclast formation and bone resorption. TRAcP staining, F-actin belt formation, and pit formation were employed for assessing the osteoclast function. Western blot, qPCR, network pharmacology, and docking analyses were used for analyzing the expression of osteoclast-associated genes and related signaling pathways. The study focused on investigating how Cor affected OVX-induced trabecular bone loss by using a mouse model. Cor could weaken osteoclast formation and function by affecting the biological receptor activators of NF-κB and its ligand at various concentrations. Mechanistically, Cor inhibited the NF-κB activation, and the MAPKs pathway stimulated by RANKL. Besides, Cor enhanced the protein stability of the Nrf2, which effectively abolished the RANKL-stimulated ROS generation. According to an OVX mouse model, Cor functions in restoring bone mass, improving microarchitecture, and reducing the ROS levels in the distal femurs, which corroborated with its in vitro antiosteoclastogenic effect. The present study indicates that Cor may restrain osteoclast formation and bone loss by modulating NF-κB/MAPKs and Nrf2 signaling pathways. Cor was shown to be a potential drug candidate that can be utilized for the treatment of osteoporosis.

Identification of PKM2 as a pyroptosis-related key gene aggravates senile osteoporosis via the NLRP3/Caspase-1/GSDMD signaling pathway.

BACKGROUNDS: Senile osteoporosis-alternatively labeled as skeletal aging-encompasses age-induced bone deterioration and loss of bone microarchitecture. Recent studies have indicated a potential association between senile osteoporosis and chronic systemic inflammation, and pyroptosis in bone marrow-derived mesenchymal stem cells is speculated to contribute to bone loss and osteoporosis. Therefore, targeting pyroptosis in stem cells may be a potential therapeutic strategy for treating osteoporosis. METHODS: Initially, we conducted bioinformatics analysis to screen the GEO databases to identify the key gene associated with pyroptosis in senile osteoporosis. Next, we analyzed the relationship between altered proteins and clinical data. In vitro experiments were then performed to explore whether the downregulation of PKM2 expression could inhibit pyroptosis. Additionally, an aging-related mouse model of osteoporosis was established to validate the efficacy of a PKM2 inhibitor in alleviating osteoporosis progression. RESULTS: We identified PKM2 as a key gene implicated in pyroptosis in senile osteoporosis patients through bioinformatics analysis. Further analyses of bone marrow and stem cells demonstrated significant PKM2 overexpression in senile osteoporosis patients. Silencing PKM2 expression inhibited pyroptosis in senile stem cells, of which the osteogenesis potential and angiogenic function were also primarily promoted. Moreover, the results in vivo demonstrated that administering PKM2 inhibitors suppressed pyroptosis in senile osteoporosis mice and mitigated senile osteoporosis progression. CONCLUSION: Our study uncovered PKM2, a key pyroptosis marker of bone marrow mesenchymal stem cells in senile osteoporosis. Shikonin, a PKM2 inhibitor, was then identified as a potential drug candidate for the treatment of osteoporosis.