The physiologically hypoxic intervertebral disc and cartilage rely on the hypoxia-inducible factor (HIF) family of transcription factors to mediate cellular responses to changes in oxygen tension. During homeostatic development, oxygen-dependent prolyl hydroxylases, circadian clock proteins and metabolic intermediates control the activities of HIF1 and HIF2 in these tissues. Mechanistically, HIF1 is the master regulator of glycolytic metabolism and cytosolic lactate levels. In addition, HIF1 regulates mitochondrial metabolism by promoting flux through the tricarboxylic acid cycle, inhibiting downsteam oxidative phosphorylation and controlling mitochondrial health through modulation of the mitophagic pathway. Accumulation of metabolic intermediates from HIF-dependent processes contribute to intracellular pH regulation in the disc and cartilage. Namely, to prevent changes in intracellular pH that could lead to cell death, HIF1 orchestrates a bicarbonate buffering system in the disc, controlled by carbonic anhydrase 9 (CA9) and CA12, sodium bicarbonate cotransporters and an intracellular H+/lactate efflux mechanism. In contrast to HIF1, the role of HIF2 remains elusive; in disorders of the disc and cartilage, its function has been linked to both anabolic and catabolic pathways. The current knowledge of hypoxic cell metabolism and regulation of HIF1 activity provides a strong basis for the development of future therapies designed to repair the degenerative disc.
Loss of control of hypoxia-inducible factor 1 (HIF1) and HIF-dependent metabolic pathways can lead to intervertebral disc degeneration, whereas loss of HIF2 function is implicated in osteoarthritis.
In nucleus pulposus cells, HIF1 and HIF2 are uniquely regulated by both oxygen-dependent and oxygen-independent mechanisms involving prolyl hydroxylase domain-containing proteins (PHDs) and circadian clock genes.
Cells of the intervertebral disc possess functional mitochondria and, in nucleus pulposus cells, mitochondria undergo HIF-dependent mitophagy and fragmentation.
HIF1 maintains glycolytic and tricarboxylic acid cycle flux while simultaneously inhibiting oxidative phosphorylation in nucleus pulposus cells.
HIF1 controls intracellular H+/lactate levels via monocarboxylate transporter 4 (MCT4); conversely, the accumulated lactate is capable of stabilizing HIF proteins by inhibiting PHD function as well as controlling transcriptional programmes.
In addition to the well-studied proton extrusion mechanisms, the intracellular pH in nucleus pulposus cells is maintained by a HIF-dependent bicarbonate buffering mechanism controlled by various components including carbonic anhydrases.
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The work of M.V.R. and E.S. is supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): R01-AR055655 and AR074813 (M.V.R.) and R01-AR074079 and AR073022 (E.S.). The work of E.S.S. is supported by grant T32-AR052273. The authors would like to thank all scientists who contributed to the data and discoveries described in this Review.
The authors declare no competing interests
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- Tricarboxylic acid (TCA) cycle
A series of chemical reactions following the oxidation of acetyl-CoA. This cycle generates biosynthetic intermediates, reducing agents and CO2, which support multiple cellular reactions. In aerobic cells, NADH generated by the TCA cycle is oxidized in the electron transport chain via a set of reactions that generate ATP.
- Redox homeostasis
A balance of reduction and oxidation enzymatic reactions (redox) within a cell. Among many redox systems, the NAD+ to NADH ratio is essential for the redox homeostasis required for glycolysis and mitochondrial function.
- Extracellular acidification rate
The rate of change of pericellular proton (H+) production by cells as measured in vitro by a Seahorse Flux analyser.
- Oxygen consumption rate
(OCR). The rate of change of pericellular oxygen (O2) consumption by cells as measured in vitro by a Seahorse Flux analyser.
- K M
A measure of the ‘affinity’ of an enzyme or transporter for its substrate. More precisely, KM is the concentration of a substrate that is needed for an enzyme or transporter to reach its half-maximum velocity (for enzymes) or binding site occupancy (for transporters); therefore, a lower KM signifies a higher affinity.
- Intracellular acidification
Cytosolic pH of cells is tightly regulated within a physiological range. When the H+ concentration exceeds this range, due to dysregulation of H+ export and cytosolic pH buffering systems, intracellular acidification occurs.
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Silagi, E.S., Schipani, E., Shapiro, I.M. et al. The role of HIF proteins in maintaining the metabolic health of the intervertebral disc. Nat Rev Rheumatol (2021). https://doi.org/10.1038/s41584-021-00621-2