Researchers here make an interesting observation relating to the function of the nucleus pulposus cell population critical to the progression of intervertebral disc degeneration. They provide evidence suggesting that upregulation of Nrf2 can slow progression of the condition by making these cells more resilient to stress, preventing cell death and cellular senescence and consequent fibrosis, and thus reducing the pace of tissue degeneration due to cell loss or dysfunction.
A normal intervertebral disc (IVD) consists of an outer annulus fibrosus (AF) that forms a ring structure to enclose the central nucleus pulposus (NP) and is connected to adjacent vertebral bodies by the cartilaginous endplates. The NP is crucial to maintain biomechanical function of IVD by counteracting and dissipating compressive loads, which depends on the extracellular matrix (ECM) secreted by nucleus pulposus cells (NPCs). However, the NP changes from a gel-like substance into a fibrous tissue with age, resulting in the structural and functional failure of IVD. Although the molecular mechanism of these pathological changes has not been fully understood, the apoptosis and senescence of NPCs are proven to be crucial to the development of intervertebral disc degeneration (IDD).
At present, increasing studies have demonstrated that reactive oxygen species (ROS) is closely related to the apoptosis and senescence of NPCs, contributing to the initiation and progression of IDD. As the main site of intracellular ROS generation, mitochondrion is also adversely influenced by ROS. Mitochondrial dysfunction is regarded as an important factor in NPC apoptosis and senescence, and accelerates disc degeneration. Thus, the strategies that aim at antioxidation and maintenance of mitochondrial homeostasis are promising to prevent or retard IDD.
Here we present evidence that a lower level of Nrf2 is closely associated with higher grade of IDD. The apoptosis and senescence of nucleus pulposus cells (NPCs) were exacerbated by Nrf2 knockdown, but suppressed by Nrf2 overexpression under oxidative stress. Based on findings that Kinsenoside could exert multiple pharmacological effects, we found that Kinsenoside rescued the NPC viability under oxidative stress and protected against apoptosis, senescence, and mitochondrial dysfunction in a Nrf2-dependent way. Further experiments revealed that Kinsenoside activated a signaling pathway of AKT-ERK1/2-Nrf2 in NPCs. Moreover, in vivo study showed that Kinsenoside ameliorated IDD in a puncture-induced model. Together, the present work suggests that Nrf2 is involved in the pathogenesis of IDD and shows the protective effects as well as the underlying mechanism of Kinsenoside on Nrf2 activation in NPCs.