Hao Chen, n/a: No financial relationships to disclose
Introduction: High levels of reactive oxygen species (ROS) lead to progressive deterioration of mitochondrial function, resulting in tissue degeneration. In this study, we observed ROS accumulation induced nucleus pulposus cells senescence in degenerative human and rat intervertebral disc, suggesting senescence as a new therapeutic target to reverse intervertebral disc degeneration (IVDD).
Objectives: To explore effective strategies for delaying IVDD from the perspective of materials science.
Methods: Preparation of bifunctional iron sulfides (mFeSzyme), detection of characterized and enzyme-like activity of mFeSzyme. In vitro experiments were conducted to verify the toxicity of persulfide released by mFeSzyme and its supernatant on rat nucleus pulposus cells, the scavenging ability of reactive oxygen species, the effect on mitochondrial membrane potential, and the rescue effect on aging, synthesis and catabolism. The mechanism of mFeSzyme inhibiting nucleus pulposus cell senescence was screened by RNA sequencing. A rat model of coccygeal disc degeneration was established by coccygeal acupuncture, and mFeSzyme nanoflower solution or its supernatant was injected locally after the model. The protective effect of mFeSzyme on anti-oxidative stress and anti-aging disc injury in vivo was verified by intervertebral disc tissue H&E, saffranine solid green staining and immunofluorescence staining.
Results: We successfully constructed mFeSzyme, showing the ability to release abundant polysulfide and presenting strong superoxide dismutase and catalase activities, both of which have the ability to suppress ROS and maintain the tissue at physical redox level. The constructed mFeSzyme appeared with the lamellar structure and formed nano-flowers, presenting well biocompatibility. mFeSzyme significantly lowered the ROS level and rescued the damaged mitochondrial function in IVDD model both in vitro and in vivo, which rescued the nucleus pulposus cells from senescence and alleviated the inflammatory response. Furthermore, RNA-sequencing revealed ROS-p53-p21 axis was responsible for cellular senescence induced IVDD. Hence, we activated p53-p21 signaling when mFeSzyme was added into the in vitro IVDD model. As expected, the rescuing phenotype of nucleus pulposus cells senescence and the subsequently alleviated inflammatory response by mFeSzyme were abolished, confirming the role of ROS-p53-p21 axis in facilitating IVDD.
Conclusions: Our study demonstrates ROS induced nucleus pulposus cells senescence leads to IVDD and the bifunctional mFeSzyme is a potential regent to effectively reverse this process, providing a new strategy for management of IVDD.
