Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration
Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that resp...
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2021
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oai:doaj.org-article:1a45b351db8c44de82ed8f5a756b42732021-11-11T16:49:52ZActivation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration10.3390/ijms2221113551422-00671661-6596https://doaj.org/article/1a45b351db8c44de82ed8f5a756b42732021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11355https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent.Jin-Woo KimHyun-Ju AnHyunJeong YeoYunhui JeongHyeonHae LeeJusung LeeKisik NamJongheon LeeDong-Eun ShinSoonchul LeeMDPI AGarticleintervertebral discdegenerationhypoxia inducible factor-1αprotectionBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11355, p 11355 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
intervertebral disc degeneration hypoxia inducible factor-1α protection Biology (General) QH301-705.5 Chemistry QD1-999 |
| spellingShingle |
intervertebral disc degeneration hypoxia inducible factor-1α protection Biology (General) QH301-705.5 Chemistry QD1-999 Jin-Woo Kim Hyun-Ju An HyunJeong Yeo Yunhui Jeong HyeonHae Lee Jusung Lee Kisik Nam Jongheon Lee Dong-Eun Shin Soonchul Lee Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| description |
Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent. |
| format |
article |
| author |
Jin-Woo Kim Hyun-Ju An HyunJeong Yeo Yunhui Jeong HyeonHae Lee Jusung Lee Kisik Nam Jongheon Lee Dong-Eun Shin Soonchul Lee |
| author_facet |
Jin-Woo Kim Hyun-Ju An HyunJeong Yeo Yunhui Jeong HyeonHae Lee Jusung Lee Kisik Nam Jongheon Lee Dong-Eun Shin Soonchul Lee |
| author_sort |
Jin-Woo Kim |
| title |
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| title_short |
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| title_full |
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| title_fullStr |
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| title_full_unstemmed |
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration |
| title_sort |
activation of hypoxia-inducible factor-1α signaling pathway has the protective effect of intervertebral disc degeneration |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/1a45b351db8c44de82ed8f5a756b4273 |
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