Unraveling the crucial role of SDF-1 in osteoarthritis progression: IL6/HIF-1α positive feedback and chondrocyte ferroptosis.

Background: Osteoarthritis (OA) is a common joint disease with an incompletely understood pathogenesis. SDF-1, a key factor in cartilage matrix degradation, is involved in OA cartilage degeneration, yet its mechanism, especially regarding ferroptosis, remains unclear. This study focuses on elucidating the role of SDF-1-induced chondrocyte ferroptosis and the IL6/HIF-1α signalling axis in OA.

Methods: A rabbit OA model was created via SDF-1 induction. Knee cartilage tissues were sequenced and analyzed bioinformatically to identify key genes, and explore critical pathways. Clinical tissue samples were utilized to validate their clinical relevance. Furthermore, cell and rabbit models were constructed through gene interference and pathway blocking. The expression of related genes and proteins was detected by QPCR, ELISA, Western blot, and immunofluorescence. Additionally, OA and ferroptosis indicators such as cell viability, immunohistochemistry, ROS, lipid ROS, Fe, MDA, and mitochondrial morphology were evaluated to uncover the molecular mechanism by which SDF-1 regulates the IL6/HIF-1α signalling axis to mediate chondrocyte ferroptosis.

Results: Bioinformatics revealed that ferroptosis was significantly activated in SDF-1-induced OA, with IL6 and HIF-1 pathways implicated. In vitro and in vivo, SDF-1 increased the expression and secretion of MMP13 but decreased COL2A1 and ACAN in chondrocytes, leading to OA-like changes. It also suppressed the expression levels of SLC7A11 and GPX4, upregulated the gene and protein levels of ACSL4, promoted the accumulation of MDA, Fe, and ROS, and caused mitochondrial morphological changes. These ferroptosis manifestations could be alleviated by the ferroptosis inhibitor Fer-1. IL6 was an important mediator of SDF-1-induced ferroptosis, and knocking down IL6 also inhibited chondrocyte ferroptosis changes. Overexpressing IL6 (oeIL6) and using PX478 to inhibit the HIF-1 signalling pathway showed that PX478 could significantly relieve the cytotoxicity produced by the culture of oeIL6 and SDF-1, enhance chondrocyte viability, reverse the decreased expression of SLC7A11 and GPX4 caused by oeIL6, increase the expression of ACSL4, reverse the accumulation of MDA, Fe, and ROS. Moreover, PX478 could also significantly reduce the expression and secretion of IL6.

Conclusion: SDF-1 mediates chondrocyte ferroptosis via the IL6/HIF-1α positive feedback, promoting OA.