Sustained Hypoxia‐Inducible Factor 1‐Alpha Accumulation Disrupts the Articular Niche to Promote Osteoarthritis Pathogenesis

ABSTRACT

The precise role of hypoxia‐inducible factor‐1α (HIF‐1α) in osteoarthritis (OA) pathogenesis remains controversial, often debated between a protective compensatory factor and a disease mediator. Here, we demonstrate that sustained, uncoupled HIF‐1α accumulation functions as a potent, compartment‐specific pathogenic driver of joint destruction. Using genetically engineered mouse models, we reveal that chondrocyte‐specific HIF‐1α overexpression ( Acan ^CreERT2 ; Hif1αdPA ^fl/fl ) triggers spontaneous OA and exacerbates destabilization of the medial meniscus (DMM)‐induced post‐traumatic joint degeneration. Mechanistically, continuous HIF‐1α activation drives pathological angiogenesis that physically dismantles the avascular, hypoxic cartilage niche, forcing a profound metabolic dysregulation that culminates in catastrophic matrix degradation. Conversely, sustained HIF‐1α activation within the synovial and superficial cartilage compartments ( Prg4‐ GFPCreERT2 ; Hif1αdPA ^fl/fl ) drives a slowly progressive, late‐onset spontaneous OA through chronic inflammatory accumulation that actively suppresses Col2a1 expression. Furthermore, this robust inflammatory priming establishes a highly vulnerable microenvironment, whereby DMM surgery significantly accelerates the progression of trauma‐induced joint collapse. Finally, transient whole‐joint HIF‐1α induction via an intra‐articular injection of lipid nanoparticles (LNP‐mRNA) closely recapitulates these detrimental effects. Collectively, our study reconciles existing controversies by establishing sustained HIF‐1α accumulation as a spatiotemporally dynamic, broad disease amplifier across the articular ecosystem, highlighting its targeted inhibition as a promising therapeutic strategy for OA.