ALKBH5 regulates key lipid metabolites to promote osteoporosis

Osteoporosis is a prevalent metabolic bone disease. Research has found a link between N6-methyladenosine (m6A) methylation and bone metabolism. The aim of this study is to investigate the relationship between m6A methylation modification-related genes and osteoporosis, and to explore the role of plasma metabolites in this relationship. Exposure was determined using cis-expression quantitative trait loci from the expression quantitative trait locus gen consortium, and a two-sample Mendelian randomization (MR) approach was employed to analyze the causal relationship between m6A methylation-related genes and osteoporosis. Summary-data-based Mendelian randomization (SMR) analysis was conducted to enhance the reliability of the Mendelian randomization results. Using the single-cell expression quantitative trait loci dataset, we explored the relationship between m6A methylation-related genes and osteoporosis in 14 types of immune cells. Mediation analysis was performed to investigate the effects of plasma metabolites and AlkB Homolog 5 (ALKBH5) on osteoporosis. Our study identified a causal association between the ALKBH5 gene and osteoporosis (odds ratio [OR] = 1.2742, 95% confidence interval: 1.1492-1.4128, P < .05). Moreover, this relationship persists in dendritic cells (OR = 1.5527, 95% confidence interval: 1.1838-2.0365, P < .05). The levels of 1-(1-enyl-palmitoyl)-GPE (P-16:0) and the ratio of Benzoate to oleoyl-linoleoyl-glycerol (18:1 to 18:2) [2] play a mediating role in the relationship between ALKBH5 and osteoporosis, with mediation effects accounting for 15.1% and 8.7% of the total effect, respectively. These results reveal a potential link between m6A methylation-related genes and osteoporosis, providing new evidence for the investigation of pathogenic mechanisms and the exploration of therapeutic targets.