THBS2 Marks Disease-Associated Chondrocyte States in Knee Osteoarthritis Cartilage: An Integrative Transcriptomic and Genetic Study

Background/Objectives: Knee osteoarthritis (KOA) is a major cause of disability, yet the molecular links between extracellular matrix (ECM) remodeling, focal adhesion signaling, and pathological chondrocyte state transitions remain incompletely defined. We aimed to identify focal adhesion-related molecules associated with KOA and characterize their genetic, tissue-level, and single-cell features.

Methods

Global Burden of Disease (GBD) 2021 data were used only to provide epidemiologic context for KOA-related disability-adjusted life years (DALYs). Bulk transcriptomic datasets (GSE114007 and GSE169077) were analyzed for differential expression, pathway enrichment, and focal adhesion-related genes. Two-sample Mendelian randomization (MR) integrating blood-derived cis-eQTL summary statistics from eQTLGen with KOA GWAS data was used for exploratory genetic prioritization; these eQTLs were not used as a surrogate measure of cartilage THBS2 expression. THBS2 was further evaluated by expression validation, gene set enrichment, immune-related ssGSEA signature analysis, single-cell RNA sequencing (GSE255460), Slingshot pseudotime analysis, and CellChat.