NFKB2 inhibits NRG1 transcription to affect nucleus pulposus cell degeneration and inflammation in intervertebral disc degeneration

Abstract

Extracellular matrix degradation, reactive oxygen species (ROS) generation, and inflammation in nucleus pulposus (NP) cells contribute to the progression of intervertebral disc degeneration (IDD). NRGs (Neuregulins) play a vital role in the development of the nervous system. In the present study, we found that NRG1 was downregulated within degenerative intervertebral disc and NP tissues, according to both bioinformatics and experimental analyses. Within IL-1β-stimulated NP cells, we observed degenerative and inflammatory changes, including inhibited cell viability, promoted cell apoptosis and ROS accumulation, reduced collagen II and aggrecan proteins, elevated MMP-3/13 and ADAMTS-4/5 proteins, and upregulated IL-6 and TNF-α mRNA levels. Within IL-1β-stimulated NP cells, NRG1 expression was also downregulated. NRG1 overexpression attenuated, whereas NRG1 silencing aggravated IL-1β-induced degenerative and inflammatory changes. Moreover, NRG1 regulated ErbB2/3 activation, contributing to the NRG1 protective function in NP cells. NFKB2 directly targeted the promoter region of NRG1 and inhibited NRG1 expression. In IL-1β-stimulated NP cells, silencing NFKB2 attenuated, whereas silencing NRG1 aggravated the degenerative changes and inflammation; the effects of NFKB2 silencing were significantly reversed by NRG1 silencing. In conclusion, NRG1 expression is downregulated within degenerative NP tissue samples and IL-1β-stimulated NP cells. NRG1 might protect against IL-1β-induced degenerative changes and inflammation. The upregulated NFKB2 might be the reason of NRG1 downregulation in degenerative NP tissues.