Hypoxia-Inducible Factor-1α Protects Against Intervertebral Disc Degeneration Through Antagonizing Mitochondrial Oxidative Stress

Abstract

Intervertebral disc degeneration (IVDD) demonstrates a gradually increased incidence and has developed into a major health problem worldwide. The nucleus pulposus is characterized by the hypoxic and avascular environment, in which hypoxia-inducible factor-1α (HIF-1α) has an important role through its participation in extracellular matrix synthesis, energy metabolism, cellular adaptation to stresses and genesis. In this study, the effects of HIF-1α on mouse primary nucleus pulposus cells (MNPCs) exposed to TNF-α were observed, the potential mechanism was explored and a rabbit IVDD model was established to verify the protective role of HIF-1α on IVDD. In vitro results demonstrated that HIF-1α could attenuate the inflammation, apoptosis and mitochondrial dysfunction induced by TNF-α in MNPCs; promote cellular anabolism; and inhibit cellular catabolism. In vivo results demonstrated that after establishment of IVDD model in rabbit, disc height and IVD extracellular matrix were decreased in a time-dependent manner, MRI analysis showed a tendency for decreased T2 values in a time-dependent manner and supplementation of HIF-1α improved histological and imaginative IVDD while downregulation of HIF-1α exacerbated this degeneration. In summary, HIF-1α protected against IVDD, possibly through reducing ROS production in the mitochondria and consequent inhibition of inflammation, metabolism disorders and apoptosis of MNPCs, which provided a potential therapeutic instrument for the treatment of IVDD diseases.

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

“…OthersNormal IVD cells are in a hypoxic microenvironment, in which hypoxia stress can activate hypoxia inducible factor-1α (HIF-1α)mediated hypoxia response element (HRE)-dependent gene transcription to maintain IVD cell survival and metabolism 262. In vitro, HIF-1α can inhibit inflammation, metabolic disorder and apoptosis of NPCs in mice by alleviating mitochondrial dysfunction 263. In addition, TFEB acts as a member of the leucinezipper family, which promotes autophagy by inducing lysosome biogenesis and autophagosome formation 139.…”

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics

“…Conversely, normoxic conditions have been shown to result in a downregulation of HIF1A expression in NP cells, which in turn leads to an increase in ROS levels. Furthermore, the reduction of ROS in NP cells under hypoxic conditions is dependent on HIF1A, emphasizing the critical function of HIF1A in the typical survival of NP cells under hypoxic conditions ( Silagi et al, 2021 ; Madhu et al, 2023 ; Yang et al, 2023 ; Song et al, 2024 ). Therefore, combining the expression pattern of HIF1A with the results of GO enrichment analysis, we divided the total NP cells into 8 celltypes, namely, HIF1A high _NP1-2, HIF1A low _NP1-3, and NPPC1-3 ( Figures 2A, B ; Supplementary Figure S2 ).…”

Selenium-SelK-GPX4 axis protects nucleus pulposus cells against mechanical overloading-induced ferroptosis and attenuates senescence of intervertebral disc

“…Rat Primary Nucleus Pulposus Cells were extracted as previously described [ 57 , 58 ]. Briefly, we isolated nucleus pulposus tissues from lumbar discs of Sprague–Dawley rats and the cells were digested with 0.2% collagenase type II (Gibco, USA) at 37 ℃ for 8 h. The cells were then cultured in DMEM/F12 (HyClone, USA) supplemented with 10% foetal bovine serum (FBS, Gibco, USA), 1% penicillin and streptomycin (P1400, SolarBio, China) under standard incubation conditions (37 ℃, 5% CO2).…”