Oxygen and Lactate Concentrations Measured in Vivo in the Intervertebral Discs of Patients With Scoliosis and Back Pain

Bartels, Else Marie; Fairbank, Jeremy; Winlove, C. P.; Urban, Jill

doi:10.1097/00007632-199801010-00001

Cited by 211 publications

(208 citation statements)

References 27 publications

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“…NP cells are unique in their ability to adapt to their physiological environment, defined by low‐oxygen and nutrient levels (Bartels, Fairbank, Winlove, & Urban, 1998). In a recent study, Choi et al (2016) showed that NP cells activate autophagy under hypoxic conditions through a noncanonical, HIF1A, and mTOR‐independent mechanism and that this activation of autophagy was required for long‐term NP cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the severe degenerative changes in the NP, our data using both mouse models show that FOXO deletion led to cell loss and ossification in the cartilaginous EP. The EP has a pivotal role in regulating the nutritional status of the IVD and the age‐related decrease in EP permeability due to ossification has been suggested as a contributing factor in IDD (Bartels et al, 1998; Bernick & Cailliet, 1982; Wang, Battie, Boyd, & Videman, 2011). It is thus likely that reduced EP permeability secondary to EP calcification significantly contributes to the severe degeneration observed in FOXO‐deficient IVD.…”

Section: Discussionmentioning

confidence: 99%

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FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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“…In disc cells, activation of the stress sensing HSF-1 complex could be triggered by several mechanisms, which result in Hsp expression [21]. ECM degeneration may lead to an environmental trigger such as exposure of the disc cells, particularly in extruded or sequestrated states, to environmental conditions (including hydrostatic loading or oxygen tensions) different from those experienced by cells in intact discs [5,7]. Alternatively, a stress response could also be initiated by a proteotoxic stress: in this case, the presence of abnormal ECM components in the cytoplasm, such as incorrectly folded or denatured proteins.…”

Section: Discussionmentioning

confidence: 99%

Disc cell clusters in pathological human intervertebral discs are associated with increased stress protein immunostaining

et al. 2009

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Intervertebral disc (IVD) cells within the annulus fibrosus (AF) and nucleus pulposus (NP) maintain distinct functional extracellular matrices and operate within a potentially noxious and stressful environment. How disc cells respond to stress and whether stress is responsible for triggering degeneration is unknown. Disc cell proliferation and cluster formation are most marked in degenerate IVDs, possibly indicating attempts at matrix repair. In other tissues, stress proteins increase rapidly after stress protecting cell function and, although implicated in degeneration of articular cartilage, have received little attention in degenerative IVD pathologies. We have compared the distribution of stress protein immunolocalization in pathological and control IVDs. Disc tissues were obtained at surgery from 43 patients with degenerative disc disease (DDD) and herniation, and 12 controls at postmortem. Tissues were immunostained with a polyclonal antibody for heat shock factor 1 (HSF-1) and monoclonal antibodies for the heat shock proteins, Hsp27 and Hsp72, using an indirect immunoperoxidase method. Positively stained cells were expressed as a percentage of the total. Cell cluster formation was also assessed. The proportion of cells in clusters was similar in the AF (both 2%) and NP (8 and 9%) of control and DDD samples, whereas in herniated tissues this was increased (AF 12%, NP 14%). Stress antigen staining tended to be more frequent in clustered rather than in single/doublet cells, and this was significant (P \ 0.005) in both the AF and NP of herniated discs. Clustered cells, which are most common in herniated discs, may be mounting a protective response to abnormal environmental factors associated with disc degeneration. A better understanding of the stress response in IVD cells may allow its utilization in disc cell therapies.

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“…1 NP is also a completely aneural and avascular tissue; hence the microenvironment is physiologically hypoxic. [2][3][4][5] NP cells adapt to this hypoxic niche by modulating a key transcription factor, HIF1A (hypoxia inducible factor 1 a subunit), to promote cell survival, matrix synthesis, and to regulate glycolytic metabolism. [6][7][8][9][10][11][12][13] A recent study using NP-specific conditional Hif1a knockout mice also shows that HIF1A is required for postnatal NP cell survival in vivo.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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Nucleus pulposus (NP) cells reside in the avascular and hypoxic microenvironment of intervertebral discs. Importantly, many activities related to survival and function of NP cells are controlled by the HIF-family of transcription factors. We hypothesize that NP cells adapt to their hypoxic niche through modulation of macroautophagy/autophagy. In various cell types, hypoxia induces autophagy in a HIF1A-dependent fashion; however, little is known about hypoxic regulation of autophagy in NP cells. Hypoxia increases the number of autophagosomes as seen by TEM analysis and LC3-positive puncta in NP cells. Hypoxic induction of autophagy was also demonstrated by a significantly higher number of autophagosomes and smaller change in autolysosomes in NP cells expressing tandem-mCherry-EGFP-LC3B. Increased LC3-II levels were not accompanied by a concomitant increase in BECN1 or the ATG12-ATG5 complex. In addition, ULK1 phosphorylation at Ser757 and Ser777 responsive to MTOR and AMPK, respectively, was not affected in hypoxia. Interestingly, when MTOR activity was inhibited by rapamycin or Torin1, LC3-II levels did not change, suggesting a novel MTOR-independent regulation. Noteworthy, while silencing of HIF1A affected hypoxic induction of BNIP3, it did not affect LC3-II levels, indicating hypoxia-induced autophagy is HIF1-independent. Importantly, there was no change in the number of LC3-positive autophagosomes in NP-specific Hif1a null mice. Finally, inhibition of autophagic flux did not affect the glycolytic metabolism of NP cells, suggesting a possible nonmetabolic role of autophagy. Taken together, our study for the first time shows that NP cells regulate autophagy in a noncanonical fashion independent of MTOR and HIF1A signaling.

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Oxygen and Lactate Concentrations Measured in Vivo in the Intervertebral Discs of Patients With Scoliosis and Back Pain

Cited by 211 publications

References 27 publications

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

Disc cell clusters in pathological human intervertebral discs are associated with increased stress protein immunostaining

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

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