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
Highlights
The intervertebral disc (IVD) links adjacent vertebral bodies and protect against damage during extremes physical loads
prolyl 4-hydroxylase domain-containing (PHD) enzyme activity is inhibited, and Hypoxia-inducible factor (HIF)-1α is spared from polyubiquitination and proteasomal degradation, thereby allowing HIF-1α to accumulate and translocate to the nucleus, where it dimerizes with HIF-1β and binds to the hypoxia-responsive element (HRE) sequences of target gene promoters
Richardson et al [17] showed that HIF-1α, glucose transporter (GLUT)-1, GLUT-3, and GLUT-9 were co-expressed in normal human IVDs, and an increase in HIF-1α expression was associated with an increase in the expression of GLUT-1, GLUT-3, and GLUT-9 in nucleus pulposus (NP) cells; this association has not been observed in annulus fibrosus (AF) cells
Summary
The intervertebral disc (IVD) links adjacent vertebral bodies and protect against damage during extremes physical loads. IVD degeneration is characterized by a cascade of cellular, compositional, structural, and functional changes [11,12]. Oxygen reaches the NP predominantly through diffusion, thereby imposing a hypoxic state on the NP cells [15,16], which is in turn enhanced by the loss of CEP permeability during IVD degeneration [17]. 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 [19,20,21,22,23,24,25,26]. HIF-1α is essential for NP development and homeostasis and could be involved in IVD degeneration in humans [34,35]. We discuss the regulatory roles of HIF-1α in the biological behaviors of IVD, current data on the expression of HIF-1α in IVD, and roles of HIF-1α plays in the regulation of the phenotypes, survival, metabolism, regulation of extra cellular matrix, and dystrophic mineralization of NP cells of IVD
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