Statins Regulate Stem Cell Growth Factor-β to Balance Osteogenesis and Adipogenesis in Mesenchymal Stem Cells,...

Dyslipidaemia has been implicated in osteonecrosis through some clinical studies. However, a direct causal relationship between hyperlipidaemia and osteonecrosis remains unconfirmed, and whether lipid-lowering agents could be used to treat osteonecrosis remains unclear. This study aimed to investigate the causal role of lipid traits in osteonecrosis using Mendelian randomisation (MR) analysis, assess the potential effects and mechanisms of lipid-lowering drug targets on osteonecrosis risk and validate these findings through experimental approaches. Genome-wide association study (GWAS) data were used to analyse lipid traits, drug targets and FinnGen osteonecrosis. Statin effects were further studied in a rat model of steroid-induced osteonecrosis and in vitro cell models. MR analysis revealed a significant association between LDL-C and increased osteonecrosis risk. Genetic mimicry of HMGCR inhibitors was associated with reduced osteonecrosis risk, which was validated through colocalisation. Stem cell growth factor-β (SCGF-β) was identified as a mediator of 21.3% of HMGCR inhibitors' effect on osteonecrosis risk. Further studies confirmed simvastatin's alleviating effect on SONFH, suggesting that simvastatin promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells (MSCs), partly mediated by SCGF-β upregulation, which activates the Wnt signalling pathway. Our findings supported dyslipidaemia as a causal factor for osteonecrosis, highlighting HMGCR as a promising therapeutic target.