Identifying Potential Drug Targets in the Knee Osteoarthritis: Insights from the Druggable Genome

The aim of this study was to find potential drug targets of knee osteoarthritis (KOA) through druggable genome and Mendelian randomization (MR) analysis. Through integrating data from expression quantitative trait loci at different tissue and cellular levels, we identified potential therapeutic targets for KOA using drug target MR and single-cell MR analyses. Based on peripheral protein quantitative trait locus (pQTL) data, we validated the identified targets at the proteomic level using summary data-based MR and Heterogeneity in Dependent Instrument tests. Meanwhile, we used mediation MR analysis to explore possible mechanisms of action of the identified targets in KOA. To capture tissue specificity, we further applied the genetically informed spatial mapping (gsMap) framework, integrating KOA genome-wide association studies with spatial transcriptomics of E16.5 mouse embryonic tissues. We identified 12 and 5 potential therapeutic targets for KOA from peripheral and central tissues, respectively. Mitogen-activated protein kinase (MAPK3) and MARK3 were validated at the proteomic level, with MAPK3 showing a genetic association with reduced risk against KOA in both peripheral and central tissues. Single-cell MR analysis revealed that Lymphocyte antigen 6 D (LY6D) was associated with an increased risk of KOA in exogenous cells, MAPK3 showed a protective association in inhibitory neuron cells, and transforming growth factor alpha (TGFA) was associated with a reduced risk of KOA in oligodendrocyte precursor cells. Mediation MR analysis showed that body mass index (BMI) played a 16.6% mediating role in the causal association between MAPK3 and KOA. GsMap analysis revealed significant enrichment of KOA signals in cartilage primordium, cartilage, lung, and brain tissues. Finally, we proposed 16 potential therapeutic targets for KOA from both central and peripheral perspectives. Meanwhile, we found that BMI served as a mediator to mediate the causal effect between MAPK3 and KOA. Further experiments are needed in the future to verify the mechanism of action of the targets identified in this study in KOA.