Specific PFKFB3 Inhibitor Memorably Ameliorates Intervertebral Disc Degeneration via Inhibiting NF-κB and MAPK Signaling Pathway and Reprogramming of Energy Metabolism of Nucleus Pulposus Cells

Abstract

Intervertebral disc (IVD) degeneration (IVDD) is a characteristic of the dominating pathological processes of nucleus pulposus (NP) cell senescence, abnormal synthesis and irregular distribution of extracellular matrix (ECM), and tumor necrosis factor-α (TNF-α) induced inflammation. Nowadays, IVD acid environment variation which accelerates the pathological processes mentioned above arouses researchers’ attention. KAN0438757 (KAN) is an effective inhibitor of selective metabolic kinase phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) that has both energy metabolism reprogramming and anti-inflammatory effects. Therefore, a potential therapeutic benefit of KAN lies in its ability to inhibit the development of IVDD. This study examined in vitro KAN toxicity in NP primary cells (NPPs). Moreover, KAN influenced tumor necrosis factor-α (TNF-α) induced ECM anabolism and catabolism; the inflammatory signaling pathway activation and the energy metabolism phenotype were also examined in NPPs. Furthermore, KAN’s therapeutic effect was investigated in vivo using the rat tail disc puncture model. Phenotypically speaking, the KAN treatment partially rescued the ECM degradation and glycolysis energy metabolism phenotypes of NPPs induced by TNF-α. In terms of mechanism, KAN inhibited the activation of MAPK and NF-κB inflammatory signaling pathways induced by TNF-α and reprogramed the energy metabolism. For the therapeutic aspect, the rat tail disc puncture model demonstrated that KAN has a significant ameliorated effect on the progression of IVDD. To sum up, our research successfully authenticated the potential therapeutic effect of KAN on IVDD and declaimed its mechanisms of both novel energy metabolism reprogramming and conventional anti-inflammation effect.

POSTN knockdown suppresses IL‐1β‐induced inflammation and apoptosis of nucleus pulposus cells via inhibiting the NF‐κB pathway and alleviates intervertebral disc degeneration

“…The NF‐κB pathway, which is intricately associated with inflammation and apoptosis, has been demonstrated to play a crucial role in IVDD 30 . In a recent investigation by Cao et al., 55 it was reported that inhibition of the NF‐κB pathway led to reprogramming of the energy metabolism in NPCs. Furthermore, Zheng et al 56 .…”

Piezo channels as molecular gatekeepers: A review of their involvement in alzheimer\'s disease

“…Mechanistically, Piezo1 exerts an anti-inflammatory effect by inhibiting the NF-κB pathway, without impacting the extracellular signal-regulated kinase (ERK) and p38 pathways. 15 This anti-inflammatory influence is demonstrated through the inhibition of LPS-induced microglial activation and the production of pro-inflammatory factors TNF-α and IL-6. However, conflicting results have been reported regarding the impact of Piezo1 activation on pro-inflammatory cytokine release, with studies indicating both inhibitory and stimulatory effects depending on the experimental conditions, including the concentration of the Piezo1 activator Yoda.…”