Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration

• Published in: International journal of molecular sciences Vol. 22; no. 21; p. 11355
• Main Authors: Kim, Jin-Woo, An, Hyun-Ju, Yeo, HyunJeong, Jeong, Yunhui, Lee, HyeonHae, Lee, Jusung, Nam, Kisik, Lee, Jongheon, Shin, Dong-Eun, Lee, Soonchul
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.10.2021; MDPI
• Subjects: Adenosine triphosphate; Aggrecan; Animals; Apoptosis; ATP; Cell Line; Cell lines; Chemical compounds; Collagen; Collagen (type II); Collagen Type II - metabolism; Degeneration; Enzymes; FasL protein; Fluoroscopy; Gene expression; Gene Expression - genetics; Gene Expression Regulation - genetics; Gene transfer; Glycolysis; Histology; Humans; Hypoxia; hypoxia inducible factor-1α; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - pharmacology; Hypoxia-inducible factor 1a; Immunohistochemistry; intervertebral disc; Intervertebral Disc - pathology; Intervertebral Disc Degeneration - prevention & control; Intervertebral discs; Lysis; Magnetic resonance imaging; Male; Morphology; Mutation; Nuclei (cytology); Nucleus pulposus; Nucleus Pulposus - metabolism; Oxygen tension; Pharmacology; Point mutation; protection; Proteins; Rats; Rats, Sprague-Dawley; Segments; Signal transduction; Signal Transduction - physiology; Sox9 protein; Spinal stenosis; Vascular endothelial growth factor; hypoxia inducible factor-1α; intervertebral disc; protection; degeneration
• DOI: 10.3390/ijms222111355
• ISSN: 1422-0067; 1661-6596

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.