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ObjectiveFibroblast growth factor 21 (FGF21) is a secreted protein that regulates body metabolism. In recent years, many observational studies have found that FGF21 is closely related to bone mineral density and osteoporosis, but the causal relationship between them is still unclear. Therefore, this study used two-sample, mediated Mendelian randomization (MR) analysis to explore the causal relationship between FGF21 and osteoporosis and bone mineral density.MethodsWe conducted a two-sample, mediator MR Analysis using genetic data from publicly available genome-wide association studies (GWAS) that included genetic variants in the inflammatory cytokine FGF21, and Total body bone mineral density, Heel bone mineral density, Forearm bone mineral density, Femoral neck bone mineral density, osteoporosis. The main analysis method used was inverse variance weighting (IVW) to investigate the causal relationship between exposure and outcome. In addition, weighted median, simple median method, weighted median method and MR-Egger regression were used to supplement the explanation, and sensitivity analysis was performed to evaluate the reliability of the results.ResultsMR Results showed that FGF21 overexpression reduced bone mineral density: Total body bone mineral density (OR=0.920, 95%CI: 0.876-0.966), P=0.001), Heel bone mineral density (OR=0.971, 95%CI (0.949-0.993); P=0.01), Forearm bone mineral density (OR=0.882, 95%CI(0.799-0.973); P=0.012), Femoral neck bone mineral density (OR=0.952, 95%CI(0.908-0.998), P=0.039); In addition, it also increased the risk of osteoporosis (OR=1.003, 95%CI (1.001-1.005), P=0.004). Sensitivity analysis supported the reliability of these results. The effect of FGF21 overexpression on osteoporosis may be mediated by type 2 diabetes mellitus and basal metabolic rate, with mediating effects of 14.96% and 12.21%, respectively.ConclusionsOur study suggests that the overexpression of FGF21 may lead to a decrease in bone mineral density and increase the risk of osteoporosis, and the effect of FGF21 on osteoporosis may be mediated through type 2 diabetes and basal metabolic rate. This study can provide a reference for analyzing the potential mechanism of osteoporosis and is of great significance for the prevention and treatment of osteoporosis.

Abstract Objective Lumbar disc herniation (LDH) is a common spinal surgical disease. Low back and leg pain caused by LDH is the main factor leading to functional disability, which has caused a serious burden to patients and society. Osteoking can delay the progression of osteoporosis and osteoarthritis, and even has a significant effect on the prevention of deep vein thrombosis after fracture surgery. In recent years, it has been gradually used in the treatment of LDH and has received significant results. However, the underlying mechanism remains unclear. The aim of this study was to predict the mechanism of Osteoking in the treatment of LDH through network pharmacology and verify it by molecular docking method. Methods The TCMSP database was used to collect the relevant active components and targets of Osteoking, while the GeneCards, OMIM and DisGeNET databases were utilized to collect the relevant disease targets of LDH. The Venny 2.1.0 software was employed to obtain the intersecting gene targets of Osteoking and LDH. PPI network construction and core target selection were performed using Cytoscape 3.9.0 software. The Metascape database was used for GO and KEGG enrichment analysis of the relevant targets. Finally, molecular docking was conducted using AutoDock software. Results The study identified 116 potential targets and 26 core targets for the treatment of LDH with Osteoking. Pathways in cancer, Alzheimer's disease, microRNAs in cancer and the IL-17 signalling pathway were among the main involved signalling pathways. Molecular docking results demonstrated that the key targets AKT1, IL-6, ALB, TNF and IL-1β exhibited relatively stable binding activities with the main active components of Osteoking. Conclusions Osteoking can alleviate the symptoms of lumbar disc herniation through the modulation of multiple targets and signalling pathways.