Hypoxic Regulation of Nucleus Pulposus Cell Survival: From Niche to Notch

This minireview examines the role of hypoxia, and hypoxia inducible factors (HIF-1 and HIF-2), in regulating the metabolism, function, and fate of cells of the nucleus pulposus in the intervertebral disk. We focus on the mechanisms by which both these hypoxia-sensitive transcription factors influence energy metabolism, radical dismutation, and expression of survival proteins. In addition, we discuss how cells of the nucleus respond to a number of hypoxia-sensitive proteins, including galectin-3, Akt, and VEGF. Where applicable, these discussions are extended to include the impact of these molecules and hypoxia on degenerating resident cells in the intervertebral niche. Finally, because the notch signaling pathway is responsive to hypoxia, we speculate that in the intervertebral niche, notch proteins participate in the regulation of disk precursor cell proliferation and differentiation. We predict that knowledge of each of these interactive proteins within the disk niche could be used to enhance renewal and promote differentiation and function of cells of the nucleus pulposus.