Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase (AXL)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Objective:To evaluate the feasibility of using cortical bone trajectory (CBT) screws in the osteoporotic thoracolumbar fixation by comparing the bone CT values at the bone-screw interface between traditional trajectory (TT) screws and CBT screws in patients with different bone densities.Methods:The high-resolution CT imaging data of thoracolumbar segments following thoracic or lumbar spine fractures from April 2020 to October 2022 were collected at The Second Hospital Affiliated to Wenzhou Medical University for retrospective analysis. They were divided into 3 groups: a normal bone mass group, an osteopenia group and an osteoporosis group. From each group 30 cases were chosen (90 cases in total, 36 males and 54 females). All the data were imported into Mimics 18.0 for three-dimensional bone reconstruction in which placement of TT and CBT screws was simulated on the vertebrae from T10 to L2 (non-fractured vertebrae). Regions of interest (ROI) where each simulated screw intersected the bone were segmented to measure their CT bone values. For each vertebra in each group, the relative difference percentage in average CT value of ROI between TT and CBT screws was calculated. The CT values of ROI were compared in the same group between TT and CBT screws from T10 to L2; the CT values of ROI were compared in the same screws among the 3 groups from T10 to L2; the CT values of ROI were compared between the CBT screws in the osteopenia and osteoporosis groups and the TT screws in the normal bone mass group; the relative difference percentages in average CT value of ROI between CBT and TT screws were compared between the 3 groups from T10 to L2.Results:The average CT value of ROI for CBT screws was significantly higher than that for TT screws from T10 to L2 in every group ( P< 0.001); as for the CT values of ROI for CBT and TT screws from T10 to L2, the osteoporosis group0.05). At T10, T12, and L1, the relative difference percentage in average CT value of ROI between CBT and TT screws was significantly higher in the osteopenia and osteoporosis groups than that in the normal bone mass group ( P<0.05), but there was no such a difference between the osteopenia and the osteoporosis groups ( P>0.05). At T11 and L2, there was no significant difference between the 3 groups in the relative difference percentage in average CT value of ROI between CBT and TT screws ( P>0.05). Conclusions:As bone mass decreases, both CBT and TT screws lead to a significant decrease in the bone density at the bone-screw interface. In patients with osteoporosis, CBT screws can still lead to a higher bone density at the bone-screw interface than TT screws, thus providing a higher strength at the bone-screw interface.