Endothelial regulators in the infrapatellar fat pad of osteoarthritis revealed by integrative multi-omics and genetic causal inference

Osteoarthritis (OA) is a multifactorial degenerative joint disease involving multiple joint components, including the infrapatellar fat pad (IFP), whose role in OA pathogenesis remains poorly understood. In this study, we employed an integrative multi-omics strategy to delineate the cellular and molecular landscape of the IFP in OA. Using single-nucleus RNA sequencing (snRNA-seq) data, we identified endothelial cells as key mediators within the IFP microenvironment, exhibiting strong intercellular communication. Differentially expressed genes (DEGs) from endothelial cells were subjected to Mendelian randomization (MR) analysis, integrating expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study (GWAS) datasets. This analysis revealed family with sequence similarity 241 member A (FAM241A) and thymidine kinase 2 (TK2) as endothelial-specific causal regulators of OA, with FAM241A associated with a protective effect and TK2 with increased disease risk. Pathway analyses suggested distinct biological roles for FAM241A and TK2. Both genes demonstrated progressively increased expression along pseudotime trajectories. Spatial transcriptomics (ST) revealed region-specific expression patterns, further supporting their involvement in IFP remodeling. Collectively, this study identifies FAM241A and TK2 as novel endothelial-specific causal genes in the IFP of OA, and uncovers temporally and spatially regulated transcriptional programs. These findings provide new mechanistic insights into OA pathogenesis and propose promising targets for biomarker development and therapeutic intervention.