CGRP Regulates Nucleus Pulposus Cell Apoptosis and Inflammation via the MAPK/NF‐κB Signaling Pathways during Intervertebral Disc Degeneration

Abstract

Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.

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

“…The underlying mechanisms were also revealed. Although a lot of signaling pathways, such as NF-κB, phosphatidylinositol-3-kinase (PI3K), MAPK, and Wnt signaling pathways, had been reported to mediate ECM metabolism or cell apoptosis after inflammation stimulation in the NPPs [38][39][40][41], we mainly focus on NF-κB and MAPK signaling pathways that were reported on PFK15 research. According to the report about the decisive role of TNF-α-induced NF-κB signaling pathway activation and subsequent p-p65 nuclear translocation in the onset and development of IVDD [42,43], we performed western blot and immunofluorescence experiments to identify whether the above conclusion exists in our research and the results corroborated the inhibiting effect of KAN on NF-κB signaling pathway activation and p-p65 nuclear translocation.…”

Mesenchymal Stem Cells May Alleviate the Intervertebral Disc Degeneration by Reducing the Oxidative Stress in Nucleus Pulposus Cells

“…The most enriched biological process was Response to oxidative stress, cellular component was Cytoplasm, and molecular function was Identical protein binding. More importantly, we also investigated the potential signaling pathways involved in the repair process of NPCs cocultured with MSCs, and some of these signaling pathways have been proved to play important roles in the pathophysiology of IDD [38][39][40][41][42]. TNF signaling pathway and IL-17 signaling pathway both were inflammation-related pathways, which indicated that MSCs might reduce the oxidative stress, and then improve the inflammatory status of degenerative NPCs [38,39].…”

“…TNF signaling pathway and IL-17 signaling pathway both were inflammation-related pathways, which indicated that MSCs might reduce the oxidative stress, and then improve the inflammatory status of degenerative NPCs [38,39]. MAPK signaling pathway was another vital biolog-ical pathway in the development of IDD [40][41][42] 7 Stem Cells International degenerative NPCs cocultured with MSCs. Both relaxin and oxytocin have been demonstrated to exert important protective effects in human diseases by inhibiting the cell apoptosis [43][44][45][46][47].…”

“…TNF signaling pathway and IL-17 signaling pathway both were inflammation-related pathways, which indicated that MSCs might reduce the oxidative stress, and then improve the inflammatory status of degenerative NPCs [ 38 , 39 ]. MAPK signaling pathway was another vital biological pathway in the development of IDD [ 40 – 42 ]. Zhang et al reported that platelet-derived growth factor-BB could prevent the IDD through activating the MAPK signaling pathway [ 40 ].…”

“…Cui et al study showed that microRNA-129-5p could alleviate the IDD via blocking the LRG1-mediated p38 MAPK activation [ 41 ]. Sun et al research indicated that calcitonin gene-related peptide could regulate the apoptosis and inflammation of NPCs via the MAPK signaling pathway during the IDD [ 42 ]. For the first time, we discovered that Relaxin signaling pathway and Oxytocin signaling pathway might exert vital functions in the biological remediation of degenerative NPCs cocultured with MSCs.…”