Figure 1. Regulation of HIF-1α in hypoxic NP cells.

A) Schematic of the intervertebral disc tissue compartments and vasculature. The absence of vasculature in disc compartments makes the NP tissue physiologically hypoxic resulting in robust HIF-1α expression. B) Oxygen dependent mechanisms of HIF-α regulation. In the presence of sufficient O₂, PHD2 hydroxylates proline residues in the ODD of HIF-1α targeting it for VHL-mediated polyubiquitination and 26S proteasomal degradation. PHD2 function can be blocked by two mechanisms: 1) Lactate accumulation generates metabolic intermediates, including pyruvate and succinate, which compete with the PHD2 substrate, 2-OG, and inhibit PHD activity. 2) Class I and II HDACs directly inhibit HIF-PHD2 axis. Unlike PHD2, PHD3 serves as a cofactor for transcriptional activation of C-TAD dependent target genes. In NP cells, HIF-1 function is refractory to FIH mediated inhibition. C). Oxygen-independent mechanisms of HIF-α regulation. HIF-1α can be targeted for 26S degradation by HSP70 possibly through displacement of HSP90. In NP cells, HIF-1α is a circadian clock-regulated gene. BMAL1 and RORα synergize to upregulate N-TAD and C-TAD dependent target genes, without evidence of direct binding to HIF-α. HDAC6 is shown to recruit HSP90 as a cofactor to upregulate HIF target gene expression, whereas CCN2 was reported to block HIF-1α cofactor binding and diminish its activity.