Serum Sphingomyelin and Osteoarthritis Risk: Evidence from Mendelian Randomization, Genetic Colocalization, and a Rat Model

Background: Sphingomyelin (SM) is a major constituent of circulating lipoproteins and cell membranes, yet its role in osteoarthritis (OA) remains unclear. This study integrated Mendelian randomization (MR), genetic colocalization, and animal experiments to investigate the association of serum SM with OA risk. Methods: Using GWAS summary statistics for serum SM and four OA phenotypes, we conducted two-sample MR with inverse-variance weighting as the primary method, complemented by weighted median, MR-Egger, and weighted mode, as well as sensitivity and reverse MR analyses, and applied colocalization to identify shared genetic signals. The animal experiment comprised four groups of male Sprague–Dawley rats defined by surgical procedure (DMM or sham) and treatment (SM or vehicle), with six rats per group. Following the intervention, histology and micro-CT assessed structural joint alterations, while RT-qPCR and Western blotting examined molecular changes. Results: Genetically predicted serum SM was positively associated with overall OA (OR per SD increase, 1.039; 95% CI, 1.020–1.059), hip OA (OR, 1.147; 95% CI, 1.118–1.177), knee OA (OR, 1.035; 95% CI, 1.011–1.060), and other OA (OR, 1.029; 95% CI, 1.009–1.050). The associations were generally consistent across sensitivity analyses, with no evidence of horizontal pleiotropy or undue influence from individual variants, while reverse MR yielded no consistent evidence that genetic liability to OA affected serum SM. Twenty-one locus–outcome pairs showed strong evidence of shared genetic signals, with the strongest colocalization for knee OA at Chr6:43.26–44.26 Mb (PP.H4 = 0.999). Compared with vehicle, SM treatment exacerbated cartilage degeneration and subchondral bone microarchitecture in DMM rats. Molecularly, this phenotype was characterized by upregulated cartilage expression of Mmp13, IL-1β, Smpdl3a, and Cd36; higher MMP13 and cleaved caspase-3 protein levels; and increases in both total and phosphorylated p38. But the phosphorylated-to-total p38 ratio did not differ significantly between groups. Conclusions: Higher genetically predicted serum SM was associated with greater OA risk, while its exogenous administration exacerbated DMM-induced joint degeneration in rats, collectively positioning elevated SM as a candidate metabolic factor in OA pathogenesis.