Metabolism of the Intervertebral Disc: Effects of Low Levels of Oxygen, Glucose, and pH on Rates of Energy Metabolism of Bovine Nucleus Pulposus Cells

Bibby, Susan; Jones, Deborah; Ripley, Ruth M; Urban, Jill

doi:10.1097/01.brs.0000154619.38122.47

Cited by 262 publications

(360 citation statements)

References 48 publications

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“…Mature disc nucleus cells appear to generate ATP virtually only by glycolysis. They thus use glucose and produce lactic acid at a high rate [13,110]. Although they do not require oxygen to remain alive, cellular activity and matrix synthesis is reduced significantly at low oxygen concentrations [42,47].…”

Section: Disc Nutritionmentioning

confidence: 99%

Tissue engineering and the intervertebral disc: the challenges

2008

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Disc degeneration is a common disorder. Although the back pain that can develop in association with this is rarely life-threatening, the annual cost in terms of morbidity, lost productivity, medical expenses and workers' compensation benefits is significant. Surgical intervention as practised currently is directed towards removing the damaged or altered tissue. Development of new treatment modalities is critical as there is a growing consensus that the strategies used currently for symptomatic degenerative disc disease may not be effective. Accordingly, there is a need to develop an entirely new way to treat this disorder; regenerative medicine and tissue engineering approaches appear particularly promising in this regard. This paper reviews some of the challenges that currently are limiting the clinical application of this approach to the treatment of disc degeneration.

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Section: Disc Nutritionmentioning

confidence: 99%

Tissue engineering and the intervertebral disc: the challenges

2008

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“…Lactate production (19) was determined by moving beads into fresh medium for 5 hours and measuring final medium concentrations (Trinity Biotech, Abingdon, UK). Glucose uptake (absorbance at 340 nm wavelength, standard 0-1 gm/liter; Sigma-Aldrich) was calculated by measuring depletion over 5 hours from medium containing 1 gm/liter glucose (20). Production/consumption rates of lactate/glucose were reported as nmoles/million cells/hour.…”

Section: Methodsmentioning

confidence: 99%

Notochordal intervertebral disc cells: Sensitivity to nutrient deprivation

Guehring

Wilde

Sumner

et al. 2009

Arthritis & Rheumatism

119

164

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Objective. The nucleus pulposus (NP) of the intervertebral disc develops from the notochord. Humans and other species in which notochordal cells (NCs) disappear to be replaced by chondrocyte-like mature NP cells (MNPCs) frequently develop disc degeneration, unlike other species that retain NCs. The reasons for NC disappearance are unknown. In humans, the change in cell phenotype (to MNPCs) coincides with changes that decrease nutrient supply to the avascular disc. We undertook this study to test the hypothesis that the consequent nutrient stress could be associated with NC disappearance.Methods. We measured cell densities and metabolic rates in 3-dimensional cultures of porcine NCs and bovine MNPCs, and we determined survival rates under conditions of nutrient deprivation. We used scanning electron microscopy to examine end plate porosity of discs with NCs and those with MNPCs. Nutrientmetabolite profiles and cell viability were calculated as a function of cell density and disc size in a consumption/ diffusion mathematical model.Results. NCs were more active metabolically and more susceptible to nutrient deprivation than were MNPCs. Hypoxia increased rates of glycolysis in NCs but not in MNPCs. Higher end plate porosity in discs with NCs suggested greater nutrient supply in keeping with higher nutritional demands. Mathematical simulations and experiments using an analog disc diffusion chamber indicated that a fall in nutrient concentrations resulting from increased diffusion distance during growth and/or a fall in blood supply through end plate changes could instigate NC disappearance.Conclusion. NCs demand more energy and are less resistant to nutritional stress than MNPCs, which may shed light on the fate of NCs in humans. This provides important information about prospective NC tissue engineering approaches.The intervertebral discs are cartilaginous structures interspersed between the vertebral bodies, providing flexibility to the spinal column. They consist of 3 regions: the outer annulus fibrosus (AF) surrounding the inner nucleus pulposus (NP) and a thin hyaline cartilaginous end plate lying between the disc and the adjacent vertebral bodies. The AF and NP differ in developmental origin, with the annulus arising from the mesenchyme and the nucleus from the notochord (1,2). During development the highly hydrated NP is populated by clusters of large vacuolated notochordal cells (NCs) of distinct molecular phenotype (2,3). In humans and some other species (e.g., cattle, chondrodystrophoid dogs) but not in others (e.g., rodents, pigs), NCs disappear before maturity to be replaced by chondrocyte-like cells of unknown provenance (here called mature NP cells [MNPCs]), which synthesize a more collagenous and less hydrated matrix (1,4-6).

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“…Importantly, the disc microenvironment is characterised by low oxygen (5%-1%) (Bartels et al, 1998), low glucose (<5mM) (Bibby et al, 2005) and low pH conditions (Bartels et al, conditions may be due to downregulation of ANK, a pyrophosphate transporter known to be involved in controlling mineralization, which is negatively regulated by both HIF1 and HIF2 (Skubutyte et al, 2010). Therefore, it is highly unlikely that the native disc environment could provide the necessary biochemical cues to promote osteogenesis, although this would need to be confirmed using animal models.…”

Section: Discussionmentioning

confidence: 99%

“…(Buckley et al, 2010;Freyria and Mallein-Gerin, 2012;Scotti et al, 2012;Twu et al, 2014). In addition, an important consideration is the harsh microenvironment within the degenerated intervertebral disc, which is characterised by reduced oxygen (Grunhagen et al, 2006) and reduced glucose concentration, (Bibby et al, 2005) creating a challenge in maintaining viable cellular populations (Antoniou et al, 1996). For chondrocytes, tissue specific oxygen gradients have been shown to play an important role in maintaining tissue phenotype through the hypoxia inducible factor (HIF) family of nuclear regulatory elements (Malda et al, 2003) in a similar manner to TGF-β supplementation through MEK/ERK and PI3k/Akt pathways (Pratsinis et al, 2012;Risbud et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

In vitro extracellular matrix accumulation of nasal and articular chondrocytes for intervertebral disc repair

Vedicherla

Buckley

2017

Tissue and Cell

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Chondrocyte based regenerative therapies for intervertebral disc repair such as Autologous Disc Cell Transplantation (ADCT, CODON) and allogeneic juvenile chondrocyte implantation (NuQu®, ISTO Technologies) have demonstrated good outcomes in clinical trials. However concerns remain with the supply demand reconciliation and issues surrounding immunoreactivity which exist for allogeneic-type technologies. The use of stem cells is challenging due to high growth factor requirements, regulatory barriers and differentiation towards a stable phenotype. Therefore, there is a need to identify alternative non-disc cell sources for the development and clinical translation of next generation therapies for IVD regeneration. In this study, we compared Nasal Chondrocytes (NC) as a non-disc alternative chondrocyte source with Articular Chondrocytes (AC) in terms of cell yield, morphology, proliferation kinetics and ability to produce key extracellular matrix components under 5% and 20% oxygen conditions, with and without exogenous TGF-β supplementation.Results indicated that NC maintained proliferative capacity with high amounts of sGAG and lower collagen accumulation in the absence of TGF-β supplementation under 5% oxygen conditions. Importantly, osteogenesis and calcification was inhibited for NC when cultured in IVD-like microenvironmental conditions. The present study provides a rationale for the exploration of nasal chondrocytes as a promising, potent and clinically feasible autologous cell source for putative IVD repair strategies.

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Metabolism of the Intervertebral Disc: Effects of Low Levels of Oxygen, Glucose, and pH on Rates of Energy Metabolism of Bovine Nucleus Pulposus Cells

Abstract: Disc cell metabolism in air and at pH 7.4 differs markedly from that found in the disc nucleus in vivo, where low levels of oxygen, glucose, and pH all coexist.

Cited by 262 publications

References 48 publications

Tissue engineering and the intervertebral disc: the challenges

Tissue engineering and the intervertebral disc: the challenges

Notochordal intervertebral disc cells: Sensitivity to nutrient deprivation

In vitro extracellular matrix accumulation of nasal and articular chondrocytes for intervertebral disc repair

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