The intervertebral disc is a prime example of tissue adaptation to metabolic and mechanical extremes. As the largest avascular organ in the human body, the disc and the central nucleus pulposus (NP) endure constant compressive loading while sustaining a hypoxic, relatively acidic, and hyperosmotic microenvironment that would be inhospitable to most cell types. Over the past two decades, work from my laboratory has revealed extraordinary details of this type of adaptation, that hypoxia-inducible factors (HIFs), particularly HIF-1α, serve as master regulators of NP cell survival, metabolism, and matrix homeostasis. This review chronicles the scientific and personal journey that began with a single unexpected observation: the normoxic stabilization of HIF-1α in NP cells. That finding grew into a substantial understanding of oxygen-independent HIF regulation and biology in the disc. Through sustained collaborations with Irving Shapiro and other colleagues and a succession of talented trainees, we demonstrated that HIF-1α is indispensable for disc development and homeostasis. In contrast, HIF-2α plays a distinct, largely opposing role, promoting matrix catabolism and fibrosis. Our work has revealed the molecular architecture underlying the disc's adaptation to avascularity, encompassing HIF-dependent regulation of glycolytic enzymes, glucose transporters, carbonic anhydrases CA9 and CA12, monocarboxylate transporter 4 (MCT4), and BNIP3-mediated mitophagy, and has opened promising therapeutic avenues for disc regeneration. Recently, we discovered that NP-derived lactate exported via MCT4 is actively imported primarily by vertebral endplate cells, and, to a lesser extent, by annulus fibrosus cells via MCT1, where it serves dual roles as a TCA metabolite and an epigenetic regulator through lactylation. This review celebrates the intellectual journey, the collaborative spirit that sustained it, and the honor of the Alexander von Humboldt Research Award, while providing a synthesis of HIF biology in the intervertebral disc spanning the discovery of oxygen by Priestley 1774 to the 2019 Nobel Prize and beyond.
