Connective tissue research · 2025
PELI1 silencing delays intervertebral disc degeneration by impeding nucleus pulposus cell death.
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Wei Xiaodong, Yu Chao, Wang Jingjie
Аннотация
PURPOSE: Intervertebral disc degeneration (IDD) is a spinal condition that causes low back pain. Pellino E3 ubiquitin protein ligase 1 (PELI1) expression reportedly correlates with inflammation and cell death. This study aimed to determine its potential role in IDD.
METHODS: Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, senescence-associated β-galactosidase staining, morphological observation, lactate dehydrogenase (LDH) release assay, quantitative reverse transcriptase polymerase chain reaction, and western blotting were used to examine the effect of PELI1 on tumor necrosis factor alpha (TNF-α)-induced human primary nucleus pulposus cells (hNPCs).
RESULTS: PELI1 was highly expressed in TNF-α-treated hNPCs. TNF-α treatment notably reduced hNPCs viability and proliferation, but enhanced senescence (elevated p16 and p21 expression), extracellular matrix degeneration (reduced collagen II and aggrecan expression and upregulated matrix metallopeptidase-13 and a disintegrin and metalloproteinase with thrombospondin type 1 motifs-5 expression), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome formation (enhanced NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and cleaved caspase 1 expression), pyroptosis (elevated cleaved gasdermin D expression), LDH release, and inflammatory cytokine release (high mobility group box 1, interleukin (IL)-1β, and IL-18). These effects were distinctly reduced by PELI1 silencing but enhanced by its overexpression. Interestingly, the effects triggered by PELI1 silencing were partially reversed by ASC overexpression.
CONCLUSIONS: PELI1 May promote IDD progression by expediting nucleus pulposus cell death and participates in the inflammatory response regulated by the NLRP3 inflammasome in nucleus pulposus cells. These suggest PELI1 as a potential therapeutic target for the treatment of IDD.
METHODS: Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, senescence-associated β-galactosidase staining, morphological observation, lactate dehydrogenase (LDH) release assay, quantitative reverse transcriptase polymerase chain reaction, and western blotting were used to examine the effect of PELI1 on tumor necrosis factor alpha (TNF-α)-induced human primary nucleus pulposus cells (hNPCs).
RESULTS: PELI1 was highly expressed in TNF-α-treated hNPCs. TNF-α treatment notably reduced hNPCs viability and proliferation, but enhanced senescence (elevated p16 and p21 expression), extracellular matrix degeneration (reduced collagen II and aggrecan expression and upregulated matrix metallopeptidase-13 and a disintegrin and metalloproteinase with thrombospondin type 1 motifs-5 expression), nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome formation (enhanced NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and cleaved caspase 1 expression), pyroptosis (elevated cleaved gasdermin D expression), LDH release, and inflammatory cytokine release (high mobility group box 1, interleukin (IL)-1β, and IL-18). These effects were distinctly reduced by PELI1 silencing but enhanced by its overexpression. Interestingly, the effects triggered by PELI1 silencing were partially reversed by ASC overexpression.
CONCLUSIONS: PELI1 May promote IDD progression by expediting nucleus pulposus cell death and participates in the inflammatory response regulated by the NLRP3 inflammasome in nucleus pulposus cells. These suggest PELI1 as a potential therapeutic target for the treatment of IDD.