Multi-omics Mendelian randomization and experimental validation suggest MAPK3 as a potential drug target for knee osteoarthritis

Knee osteoarthritis (KOA) is a major cause of pain and disability, yet effective disease-modifying treatments remain limited. Endoplasmic reticulum stress contributes to joint degeneration, but genetically supported targets remain unclear. We integrated blood eQTL, plasma pQTL, and KOA GWAS data using Mendelian randomization and colocalization analyses. MAPK3 emerged as the most consistent candidate, with genetically predicted higher MAPK3 expression and ERK1 protein abundance associated with lower KOA risk and supported by colocalization evidence. In a destabilization of the medial meniscus mouse model, MAPK3/ERK1 expression was reduced in osteoarthritic joint tissues and chondrocytes. To assess its biological function, MAPK3/ERK1 was bidirectionally manipulated in IL-1β-treated primary murine chondrocytes. ERK1 overexpression partially restored IL-1β-reduced COL2 expression and suppressed MMP13 induction, whereas MAPK3/ERK1 silencing further decreased COL2 and increased MMP13. These reciprocal effects support a role for MAPK3/ERK1 in maintaining the balance between extracellular matrix synthesis and degradation under inflammatory stress. Collectively, the genetic, in vivo expression, and in vitro functional evidence supports MAPK3/ERK1 as a genetically informed candidate protective target for further mechanistic and translational investigation in KOA.