Intervertebral disc (IVD) degeneration largely contributes to pathoanatomical and degenerative changes in spinal structures, thereby increasing the risk of low back pain. Apoptosis of nucleus pulposus (NP) cells exacerbates IVD degeneration, and an increasing number of studies have shown that interventions targeting NP apoptosis can improve IVD degeneration, demonstrating its potential as a therapeutic strategy.
Recent data indicate that advanced glycation end products (AGEs) accumulate in NP tissues concurrently with the progression of IVD degeneration and create a microenvironment of oxidative stress. We investigated whether AGEs accumulation exacerbates NP apoptosis and IVD degeneration and explored the mechanisms underlying these effects. The researchers observed that human NP cell viability and proliferation were significantly inhibited by AGE treatment, primarily due to apoptosis.
Furthermore, activation of the mitochondrial apoptotic pathway was detected after AGEs treatment. Molecular data show that AGEs can significantly exacerbate the generation of mitochondrial reactive oxygen species, prolong activation of mitochondrial permeability transition pores, and increase Bax protein levels and decrease Bcl-2 protein levels in mitochondria. The antioxidants triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1) can reduce these effects.
Researchers identified impairment of Sirtuin3 (SIRT3) function and mitochondrial antioxidant network as important mechanisms of AGE-induced oxidative stress and secondary apoptosis in human NP cells.
Finally, Nicotinamide Mononucleotide (NMN) can restore SIRT3 through the adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-gamma coactivator 1α (AMPK-PGC-1α) pathways in vitro Function and rescue human NP cell apoptosis, the researchers confirmed its protective effect on AGEs-induced IVD degeneration in vivo. Data demonstrate that SIRT3 prevents AGE-induced apoptosis and IVD degeneration in human NP cells. Targeting SIRT3 to improve mitochondrial redox homeostasis may be a potential therapeutic strategy to mitigate AGE-related IVD degeneration.
In this study, researchers reported that in vitro AGEs treatment inhibited the survival and proliferation of human NP cells by inducing oxidative stress and mitochondrial dysfunction, in which impairment of SIRT3 function and mitochondrial antioxidant network played an important role. AGEs-induced inhibition of AMPK/PCG-1α is involved in this process.
Furthermore, NMN supplementation had a protective effect against AGE-induced NP apoptosis and IVD degeneration, in part by restoring SIRT3 function and mitochondrial redox homeostasis. The findings of this study provide new insights into the mechanisms of oxidative stress and apoptosis in NP cells, with therapeutic implications for the treatment of IVD degeneration.