Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

Abstract

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

Bardoxolone Methyl Ameliorates Compression-Induced Oxidative Stress Damage of Nucleus Pulposus Cells and Intervertebral Disc Degeneration Ex Vivo

“…In particular, the NP tissue is located at the center of the IVD, and compression leads to the destruction of the IVD tissue, which causes the ability of the IVD to withstand mechanical loads to weaken. Furthermore, the physiological stress structure of the spine changes, leading to a series of spinal degenerative diseases (Wang et al, 2020b;Kim et al, 2021;. Therefore, preventing NP cell apoptosis and ECM degradation induced by oxidative stress may be effective methods for the treatment of IDD.…”

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

“…The degenerated disc was less elastic, consequently prohibiting the ability to absorb and to endure spinal loading [ 16 ]. Type II collagen in IVD was demonstrated to be present at normal levels in the NP and in the inner layer of the AF; however, type I collagen was found to be present at normal levels in the AF and degenerative NP [ 39 ].…”

“…In the nucleus, the transcriptional activity of the HIF-1α heterodimer is regulated by the hydroxylase factor inhibiting HIF-1 (FIH-1) [ 15 ]. The FIH-1 enzyme hydroxylates Asn803 on HIF-1α, which represses HIF-1α transactivation by preventing the transcriptional coactivator p300/CBP from binding to the HIF-1α C-transactivation domains (C-TADs) [ 16 , 17 ].…”

Concepts of Regeneration for Spinal Diseases in 2021

“…Kim JW et al [1] conducted a comprehensive literature review regarding the involvement and roles of hypoxia-inducible factor-1alpha (HIF-1α) in intervertebral disc degeneration. The HIF-1α is a master transcription factor that initiates a coordinated cellular cascade in response to low oxygen tension, which is then required for disc NP development and homeostasis.…”