European journal of nutrition · 2025
Vitamin D deficiency promotes intervertebral disc degeneration via p38/NCoR2-mediated extracellular matrix degradation.
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Li Xingguo, Wang Bing, Wang Xuenan, Chen Chao, Zhan Enyu, Lv Zhengpin, He Qicong, Hu Yaoquan, Zhang Fan
Аннотация
PURPOSE: Vitamin D (VD) deficiency significantly contributes to intervertebral disc degeneration (IDD), a common cause of low back pain, yet the underlying mechanisms remain unclear. This study investigates how VD deficiency exacerbates IDD and identifies potential therapeutic targets.
METHODS: We used real-time quantitative PCR, immunoblots, immunoprecipitation, liquid chromatography with tandem mass spectrometry analysis, co-immunoprecipitation, and chromatin immunoprecipitation to study gene and protein expressions, protein complex assembly, and transcriptional complex binding. Degeneration of IVDs was assessed via hematoxylin and eosin staining.
RESULTS: Eight members of ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are enriched in lumbar discs of both VD-deficient and VD receptor (VDR)-knockout (VDR-/-) mice. Sufficient VD suppresses ADAMTS genes through a complex formed by nuclear receptor corepressor 2 (NCoR2) and signal transducer and activator of transcription 6 (STAT6). VD deficiency activates p38 kinase, leading to NCoR2 phosphorylation and subsequent degradation by a Cullin 4-RING (CRL4) E3 ligase, impairing NCoR2's transrepression function and upregulating ADAMTS genes, accelerating extracellular matrix (ECM) degradation in discs. This mechanism is replicated in VDR-deficient cells. In vitro treatments with p38 inhibitor (BIRB-796) and CRL4 inhibitor (KH-4-43) reduce ADAMTS expression, and in vivo application of these inhibitors improves disc integrity in VD-deficient mice.
CONCLUSION: Our findings highlight NCoR2 degradation, mediated by p38 kinase and CRL4 E3 ligase, as crucial in VD deficiency-induced IDD. Targeting this pathway offers promising therapeutic potential to mitigate IDD progression in individuals with VD deficiency or VDR abnormalities.
METHODS: We used real-time quantitative PCR, immunoblots, immunoprecipitation, liquid chromatography with tandem mass spectrometry analysis, co-immunoprecipitation, and chromatin immunoprecipitation to study gene and protein expressions, protein complex assembly, and transcriptional complex binding. Degeneration of IVDs was assessed via hematoxylin and eosin staining.
RESULTS: Eight members of ADAMTSs (A disintegrin and metalloproteinase with thrombospondin motifs) are enriched in lumbar discs of both VD-deficient and VD receptor (VDR)-knockout (VDR-/-) mice. Sufficient VD suppresses ADAMTS genes through a complex formed by nuclear receptor corepressor 2 (NCoR2) and signal transducer and activator of transcription 6 (STAT6). VD deficiency activates p38 kinase, leading to NCoR2 phosphorylation and subsequent degradation by a Cullin 4-RING (CRL4) E3 ligase, impairing NCoR2's transrepression function and upregulating ADAMTS genes, accelerating extracellular matrix (ECM) degradation in discs. This mechanism is replicated in VDR-deficient cells. In vitro treatments with p38 inhibitor (BIRB-796) and CRL4 inhibitor (KH-4-43) reduce ADAMTS expression, and in vivo application of these inhibitors improves disc integrity in VD-deficient mice.
CONCLUSION: Our findings highlight NCoR2 degradation, mediated by p38 kinase and CRL4 E3 ligase, as crucial in VD deficiency-induced IDD. Targeting this pathway offers promising therapeutic potential to mitigate IDD progression in individuals with VD deficiency or VDR abnormalities.