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.