HIF-1α protects articular cartilage in osteoarthritis by activating autophagy

Abstract Objective Hypoxia-inducible factor-1α (HIF-1α) is known to regulate the energy metabolism and autophagy of chondrocytes under inflammatory and hypoxic conditions. This study aims to investigate the mechanisms by which HIF-1α influences cartilage injury through autophagy and oxidative stress pathways following the onset of osteoarthritis (OA). Methods Human knee joint samples were categorized into the OA group and the control group (CON) for radiological and pathological assessments, along with proteomic analysis to elucidate the interplay between osteoarthritis, HIF-1α, and autophagy. Chondrocytes were stimulated with IL-1β to establish an OA model, and these cells were subsequently divided into the control group (CON), IL-1β group (OA), IL-1β + LW6 group, IL-1β + DMOG100 group, and IL-1β + DMOG200 group. Immunofluorescence and western blot analyses were employed to measure the expression levels of HIF-1α, ROS, and LC3 to clarify the association between HIF-1α and autophagy. In addition, mice were categorized into the control group (CON), model group (DMM), and treatment group (DMM + DMOG). Immunohistochemistry, immunofluorescence, and RT-qPCR were conducted to assess the expression levels of HIF-1α, LC3, MMP-13, COL2, β-catenin, and HIF-2α. Micro-CT was utilized to evaluate subchondral bone morphology to elucidate the relationship between HIF-1α and cartilage injury, as well as its underlying mechanisms. Results Osteoarthritic cartilage exhibited elevated levels of HIF-1α, reduced LC3 expression, and increased ROS levels. Inhibition of HIF-1α using LW6 led to further reductions in LC3 levels and increased ROS production. Conversely, the activation of HIF-1α with DMOG significantly elevated HIF-1α levels, increased LC3 expression, reduced ROS levels, decreased MMP-13 levels, enhanced COL2 expression, decreased β-catenin levels, and lowered HIF-2α expression, resulting in a reduced severity of articular cartilage injury. Conclusion After the onset of osteoarthritis, low or physiologically elevated levels of HIF-1α may not adequately activate autophagy. Maintaining HIF-1α at elevated levels can protect articular cartilage by inhibiting oxidative stress and enhancing autophagy.