The Role of Autophagy and Primary Cilia in the Nucleus Pulposus
The nucleus pulposus (NP) of the intervertebral disc serves an essential load-bearing function for the spine. The lack of direct blood supply in the NP results in its physiologically hypoxic tissue microenvironment. HIF-1α is an essential transcription factor that regulates expression of numerous genes involved in NP cell survival and function. The extracellular matrix of the NP is abundant with proteoglycan aggrecan bound by sulfated glycosaminoglycan (GAG) chains. Due to the high fixed charge density of the GAG molecules, NP tissue has high osmotic swelling pressure and high osmolarity. NP cells survive and function within the hyperosmotic environment through TonEBP-mediated osmoregulation. The hypoxic and hyperosmotic niche of the NP tissue requires the resident cells to utilize various mechanisms for maintaining their health. The primary goal of this study was to investigate if NP cells modulate autophagy and primary cilia for their survival and function. Our results demonstrated that NP cells increase noncanonical autophagy under hypoxic condition in a HIF-1α- and MTOR-ULK1 axis-independent manner. This was the first report showing basal autophagy being MTOR-independent, highlighting the distinctiveness of NP cell behavior. While autophagy is important for NP cell survival, it does not have much influence on the cells’ glycolytic metabolism, suggesting a potential non-canonical function of autophagy. Additionally, we established the SM/J mouse strain as a valuable animal model that shows early spontaneous disc degeneration. The degenerative changes of SM/J mouse discs are characterized by fibrosis of the matrix as well as acquisition of hypertrophic phenotype by NP cells, which closely mimic human disc degeneration. We also demonstrated, for the first time, that NP cells have primary cilia in vitro. Despite their length being osmotically sensitive, primary cilia in NP cells do not control TonEBP activity under hyperosmotic condition. Taken together, NP cells upregulate non-canonical autophagy under hypoxic condition to promote cell survival, while NP cell primary cilia do not serve osmo-regulatory function through TonEBP activity. These results underscore the complexity as well as uniqueness of NP cell biology, in which the function and regulation of signaling pathways and organelles are often non-canonical. The knowledge gained from this study will contribute to deepening our understanding of the molecular events controlling disc cell function in health and disease.
Molecular biology|Cellular biology|Medicine
Choi, Hyowon, "The Role of Autophagy and Primary Cilia in the Nucleus Pulposus" (2019). ETD Collection for Thomas Jefferson University. AAI10831499.