SDF-1/CXCR4 axis induces apoptosis of human degenerative nucleus pulposus cells via the NF-κB pathway

Abstract

Intervertebral disc degeneration (IVDD) is a major cause of lower back pain, and increased cell apoptosis is a key characteristic of IVDD. The present study aimed to investigate the effects and mechanism of the stromal cell-derived factor-1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4) axis on apoptosis in human degenerative nucleus pulposus cells (NPCs). The expression levels of SDF-1 and CXCR4 in human intervertebral discs (IVD) were determined using immunohistochemistry and western blot analysis. Apoptosis of primary cultured NPCs was quantified by Annexin V/propidium iodide staining following stimulation with SDF-1 and knockdown of CXCR4 using small interfering RNA (siRNA). The association with the nuclear factor-κB (NF-κB) signaling pathway was investigated using CXCR4-siRNA and NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), treatment. The results demonstrated that SDF-1 and its receptor, CXCR4, were upregulated in degenerative IVD samples compared with normal samples. Stimulation with SDF-1 increased the level of apoptosis in cultured NPCs, and conversely, the apoptosis level was suppressed post-transfection with CXCR4 siRNA compared with SDF-1 stimulation alone. Furthermore, SDF-1 treatment increased the level of phosphorylated NF-κB subunit P65, which was downregulated following CXCR4 siRNA and PDTC treatment. In addition, CXCR4 siRNA and PDTC inhibited the nuclear translocation of P65, which was induced by SDF-1. Taken together, SDF-1-mediated apoptosis was suppressed by NF-κB inhibition using PDTC. In conclusion, the SDF-1/CXCR4 axis promoted cell apoptosis in human degenerative NPCs via the NF-κB pathway, thus suggesting that SDF-1/CXCR signaling may be a therapeutic target for the treatment of degenerative IVD diseases.

Hemeoxygenase-1 Suppresses IL-1β-Induced Apoptosis Through the NF-κB Pathway in Human Degenerative Nucleus Pulposus Cells

“…Inhibiting the activation of NF-κB can significantly retard the degree of disc degeneration [13, 28]. It was also reported that the SDF-1/CXCR4 axis induces apoptosis of human degenerative NPCs via the NF-κB pathway [29]. Our results also indicated that the levels of apoptosis and P65 in degenerated intervertebral disc tissue were significantly higher than in normal intervertebral disc tissue, suggesting that the NF-κB signalling pathway was involved in NPC apoptosis.…”

It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

“…The theme of the regulation of axonal plasticity by Calpain mediated mechanisms was also determined in studies involving the effect of SDF1 on axon development. SDF1 binds to the G-protein-coupled receptor C-X-C motif chemokine receptor 4 (CXCR4) (Liu et al, 2016), and regulates the development of the nervous system through effects on cell migration and axon guidance (Mithal, et al, 2012). A recent report provides evidence that SDF1 reduces branching in cortical interneuron through dual regulation of actin and microtubules.…”

lncRNAs: novel players in intervertebral disc degeneration and osteoarthritis

“…In contrast, genetic heredity is the predominant risk factor for degenerative disc disease and is estimated to cause over 70% of cases . Although the pathogenesis of IDD is not completely understood, it is well established that progressive loss of ECM, cell proliferation, inflammatory response, angiogenesis, apoptosis, autophagy, and oxidative stress play critical roles in the occurrence and development of disc degeneration …”

“…40,41 Although the pathogenesis of IDD is not completely understood, it is well established that progressive loss of ECM, cell proliferation, inflammatory response, angiogenesis, apoptosis, autophagy, and oxidative stress play critical roles in the occurrence and development of disc degeneration. [42][43][44][45][46][47] Like the well-known short non-coding RNAs such as miRNAs, 1 49 Overexpression of FAF1 is known to potentiate Fas-mediated apoptosis and suppress the degradation of ubiquitinated proteins, leading to a significant increase of cell death. 50,51 These authors also found that in addition to upregulation of the nearby enhancer-like lncRNA, RP11-296A18.3, FAF1 is significantly increased in degenerative discs compared with the normal discs.…”