Effects of Glucose Deprivation on ATP and Proteoglycan Production of Intervertebral Disc Cells under Hypoxia

Abstract

As the most common cause of low back pain, the cascade of intervertebral disc (IVD) degeneration is initiated by the disappearance of notochordal cells and progressive loss of proteoglycan (PG). Limited nutrient supply in the avascular disc environment restricts the production of ATP which is an essential energy source for cell survival and function such as PG biosynthesis. The objective of this study was to examine ATP level and PG production of porcine IVD cells under prolonged exposure to hypoxia with physiological glucose concentrations. The results showed notochordal NP and AF cells responded differently to changes of oxygen and glucose. Metabolic activities (including PG production) of IVD cells are restricted under the in-vivo nutrient conditions while NP notochordal cells are likely to be more vulnerable to reduced nutrition supply. Moreover, provision of energy, together or not with genetic regulation, may govern PG production in the IVD under restricted nutrient supply. Therefore, maintaining essential levels of nutrients may reduce the loss of notochordal cells and PG in the IVD. This study provides a new insight into the metabolism of IVD cells under nutrient deprivation and the information for developing treatment strategies for disc degeneration.

Two‐ and three‐dimensional in vitro nucleus pulposus cultures: An in silico analysis of local nutrient microenvironments

“…In some studies, high oxygen has been observed to reduce the rate of glycolysis which is known as a positive Pasteur effect 20,94 . However, a number of other studies have shown a negative Pasteur or no effect for NP cells 8,14 . Despite IVD cells preferring a more prevalent glycolytic pathway for energy in its harsh microenvironmental conditions, the reasons for differences in observed phenomenon under varying nutrient concentrations remain unclear.…”

“…Several studies have reported oxygen consumption rates (OCR), 8–10,12 glucose consumption rates (GCR), and lactate production rates (LPR) for NP cells from animals and humans under varying nutrient conditions 8,10,13,14,17,34,35 . Tabulated rates from these studies can be found in Table S2–S4.…”

“…GCR was more explicitly modeled using a maximum GCR based on the external glucose boundary conditions (as no clear and obvious difference exists between 5.5 and 25 mM in Figure 1C) but becomes rate limited at ~2 mM, by curve fitting Michaelis–Menten kinetics to experimental measurements at lower glucose concentrations (<5 mM) 14,17 where is the time (hr), is the local glucose concentration (mM), is the cell density (million cell/ml).…”

The role of microenvironment in stem cell-based regeneration of intervertebral disc

“…Some researchers have demonstrated the effect of glucose concentration on regulating the chondrogenic and osteogenic differentiation potential of CESCs to affect the differentiation of CESCs, which may represent a target for CE degeneration therapy ( Sun et al, 2019 ). Furthermore, to adapt to the changes in the microenvironment, IVD progenitors correspondingly change their metabolism by increasing matrix synthesis and anaerobic glycolysis in low glucose conditions (5 mM), which allows generating energy while producing less reactive oxygen species (ROS) and consuming less O 2 ( Yin et al, 2020 ).…”

“…No adverse events were found in clinical trials, and relief of pain was noted in the injection group compared to discectomy alone on a 2-years follow-up. Furthermore, patients who underwent discectomy and autologous disc chondrocyte transplantation were proved to have less adjacent segment disease than those who underwent discectomy alone (Yoshikawa et al, 2010). In another clinical trial, autologous MSCs were injected into the disc of 13 patients followed for 1 year as part of a pilot study.…”