Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate...

Iron overload is a common phenomenon in the elderly population. Many clinical studies have indicated an association between iron overload and the incidence and pathological progression of intervertebral disc degeneration (IVDD). However, the role and underlying mechanism by which iron participates in the progression of IVDD has not yet been reported. In the present study, we aimed to elucidate the connection between iron overload and IVDD, and explore the underlying mechanisms of disease. Firstly, a clinical epidemiology study was conducted and revealed that iron overload is an independent risk factor for human IVDD. To elucidate the role of iron overload in IVDD, an iron overload mouse model was established, and we observed that iron overload promoted IVDD and cartilage endplate degeneration in a dose dependent manner. Endplate chondrocytes were further isolated and treated with FAC to mimic iron overload in vitro. Excess iron significantly promoted mineralization of endplate chondrocytes in addition to their degeneration via oxidative stress. Moreover, a high dose of excess iron promoted chondrocytes ferroptosis. An iron chelator (DFO), an antioxidant (NAC) and a ferroptosis inhibitor (Fer-1) demonstrated effective inhibition of endplate chondrocyte degeneration induced by iron overload, and our in vivo studies further demonstrated that DFO, NAC and Fer-1 could rescue high dose iron-induced IVDD and cartilage endplate calcification. In conclusion, our results indicate that iron overload is strongly associated with the onset and development of IVDD via oxidative stress and ferroptosis. Inhibiting oxidative stress or ferroptosis could therefore be promising therapeutic strategies for IVDD induced by iron overload.