Maintaining high levels of HIF-1α protects osteoarthritis cartilage by activating autophagy.

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and subchondral bone remodeling, with hypoxia-inducible factor-1α (HIF-1α) playing a pivotal role in chondrocyte survival under hypoxic and inflammatory conditions. This study investigated the protective mechanisms of HIF-1α in OA by examining its effects on autophagy and oxidative stress in both human OA cartilage samples and murine models. Proteomic and immunohistochemical analyses revealed elevated HIF-1α expression alongside reduced autophagy markers Microtubule-Associated Protein 1 Light Chain 3(LC3) and increased cartilage damage indicators Matrix Metalloproteinase 13(MMP13), decreased Type 2 Collagen (COL2) in OA-affected tissues. In vitro experiments demonstrated that HIF-1α inhibition exacerbated oxidative stress Reactive Oxygen Species (ROS) and impaired autophagy, while HIF-1α activation (via DMOG) enhanced autophagy and reduced ROS, thereby preserving chondrocyte function. In vivo, DMOG treatment in a destabilized medial meniscus (DMM) mouse model attenuated cartilage degradation, suppressed MMP13, and restored COL2 expression. Furthermore, HIF-1α upregulation correlated with reduced β-catenin and HIF-2α levels, suggesting its role in mitigating subchondral bone sclerosis. These findings highlight that maintaining high HIF-1α levels protects OA cartilage by enhancing autophagy and inhibiting oxidative stress, offering a potential therapeutic strategy for OA management.