Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron‐mediated Fenton reactions. It has been reported that iron deficiency had been ...implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis. Our in vitro models show the changes in protein levels of ferroptosis marker and enhanced lipid peroxidation level during oxidative stress. Safranin O staining, hematoxylin‐eosin staining, and immunohistochemical were used to assess the IVDD after 8 weeks of surgical procedure in vivo. Treatment with ferrostatin‐1, deferoxamine, and RSL3 demonstrate the role of ferroptosis in tert‐butyl hydroperoxide (TBHP)‐treated annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Ferritinophagy, nuclear receptor coactivator 4 (NCOA4)‐mediated ferritin selective autophagy, is originated during the process of ferroptosis in response to TBHP treatment. Knockdown and overexpression NCOA4 further prove TBHP may induce ferroptosis of AFCs and NPCs in an autophagy‐dependent way. These findings support a role for oxidative stress‐induced ferroptosis in the pathogenesis of IVDD.
Graphical
Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron‐mediated Fenton reactions. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis.
High dose and long‐term steroid treatment can alter antioxidative ability and decrease the viability and function of osteoblasts, leading to osteoporosis and osteonecrosis. Ferroptosis, a new type of ...cell death characterized by excessive lipid peroxidation due to the downregulation of GPX4 and system Xc−, is involved in glucocorticoid‐induced osteoporosis. Endothelial cell‐secreted exosomes (EC‐Exos) are important mediators of cell‐to‐cell communication and are involved in many physiological and pathological processes. However, the effect of EC‐Exos on osteoblasts exposed to glucocorticoids has not been reported. Here, we explored the role of EC‐Exos in glucocorticoid‐induced osteoporosis. In vivo and in vitro experiments indicated that EC‐Exos reversed the glucocorticoid‐induced osteogenic inhibition of osteoblasts by inhibiting ferritinophagy‐dependent ferroptosis.
Here, we explored the role of EC‐Exos in glucocorticoid‐induced osteoporosis. In vivo and in vitro experiments indicated that EC‐Exos reversed the glucocorticoid‐induced osteogenic inhibition of osteoblasts by inhibiting ferritinophagy‐dependent ferroptosis.
The main pathological mechanism of intervertebral disc degeneration (IVDD) is the programmed apoptosis of nucleus pulposus (NP) cells. Oxidative stress is a significant cause of IVDD. Whether ...mitophagy is induced by strong oxidative stress in IVDD remains to be determined. This study aimed to investigate the relationship between oxidative stress and mitophagy and to better understand the mechanism of IVDD in vivo and in vitro. To this end, we obtained primary NP cells from the human NP and subsequently exposed them to TBHP. We observed that oxidative stress induced mitophagy to cause apoptosis in NP cells, and we suppressed mitophagy and found that NP cells were protected against apoptosis. Interestingly, TBHP resulted in mitophagy through the inhibition of the HIF-1α/NDUFA4L2 pathway. Therefore, the upregulation of mitochondrial NDUFA4L2 restricted mitophagy induced by oxidative stress. Furthermore, the expression levels of HIF-1α and NDUFA4L2 were decreased in human IVDD. In conclusion, these results demonstrated that the upregulation of NDUFA4L2 ameliorated the apoptosis of NP cells by repressing excessive mitophagy, which ultimately alleviated IVDD. These findings show for the first time that NDUFA4L2 and mitophagy may be potential therapeutic targets for IVDD.
Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone ...formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K-AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53-Nedd4-Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.
Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role ...in IVDD. As a by‐product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress‐mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD.
Graphic overview of the role of mitochondrial dysfunction in the pathogenesis of IVDD. An imbalance between ROS intercellular production and antioxidant defense capacity will directly give rise to the occurrence of oxidative stress, which is mainly represented by cell apoptosis, abnormal autophagy, cell senescence, and mitochondrial dysfunction. Among the oxidative stress‐related pathophysiological processes, mitochondrial dysfunction plays an essential role in the disc pathology of IVDD, which manifests as imbalanced dynamics and dysregulated mitophagy. ROS promotes the fusion of mitochondria, which decreases their fission process, so that disabled mitochondria can be separated from the mitochondrial pool. Further, mitophagy serves as the quality control mechanism, which can be dysregulated under the condition of oxidative stress by overwhelmingly clearing both dysfunctional and normal mitochondria. Overall, the effects of mitochondria dysfunction result in the massive disc cell death with overproduction of MMP and the degradation of ECM, eventually the pathogenesis of IVDD.
Lead thiocyanate in the perovskite precursor can increase the grain size of a perovskite thin film and reduce the conductivity of the grain boundaries, leading to perovskite solar cells with reduced ...hysteresis and enhanced fill factor. A planar perovskite solar cell with grain boundary and interface passivation achieves a steady‐state efficiency of 18.42%.
Background/Aims: Apoptosis and autophagy are two patterns of programmed cell death which play important roles in the intervertebral disc degeneration. Oxidative stress is an important factor for the ...induction of programmed cell death. However, the cellular reactions linking autophagy to apoptosis of disc cells under oxidative stress have never been described. This study investigated the responses of autophagy and apoptosis and their interactions in the nucleus pulposus cells (NP cells) under oxidative stress, with the aim to better understand the mechanism of disc degeneration. Methods: NP cells isolated from rat lumbar discs were subjected to different concentrations of H2O2 for various time periods. Cell viability was determined by CCK-8 assay, and their apoptosis and autophagy responses were evaluated by fluorescent analysis, flow cytometry and western blotting, et al. The interactions of autophagy and apoptosis and the possible signaling pathways were also investigated by using autophagy modulators. Results: H2O2 increased the lysosomal membrane permeability in the NP cells and induced apoptosis through the mitochondrial pathway subsequently. Meanwhile, H2O2 stimulated an early autophagy response through the ERK/m-TOR signaling pathway. Autophagy inhibition significantly decreased the apoptosis incidence in the cells insulted by H2O2. Conclusion: These results suggested that controlling the autophagy response in the NP cells under oxidative stress should be beneficial for the survival of the cells and probably delay the process of disc degeneration.
Abstract
Purpose
To assess the safety and efficacy of the extra-facet puncture technique applied in unilateral percutaneous vertebroplasty (PVP) for treating osteoporotic vertebral compression ...fractures.
Methods
Demographics (age, gender, body mass index and underlying diseases) were recorded for analyzing. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores as well as their corresponding minimal clinically important difference (MCID) were used to evaluate clinical outcomes. The segmental kyphotic angle, the vertebral compression ratio and bone cement distribution pattern were evaluated by the plain radiographs. The facet joint violation (FJV) was defined by the postoperative computed tomography scan. Binary logistic regression analysis was performed to investigate relationships between multiple risk factors and residual back pain.
Results
VAS and ODI scores in both traditional puncture group and extra-facet puncture group were significantly decreased after PVP surgery (
p
< 0.05). However, no significant difference was observed between the two groups according to VAS and ODI scores. The proportion of patients achieving MCID of VAS and ODI scores was higher in extra-facet puncture group as compared to traditional puncture group within a month (
p
< 0.05). Finally, multivariate logistic regression analysis showed that FJV (odds ratio 16.38,
p
< 0.001) and unilateral bone cement distribution (OR 5.576,
p
= 0.020) were significant predictors of residual back pain after PVP surgery.
Conclusions
Extra-facet puncture percutaneous vertebroplasty can decrease the risk of FJV and it also has the advantage of more satisfied bone cement distribution.
Objective
Lumbar disc degeneration (LDD) is a common cause of low back pain and disability, and its prevalence increases with age. The aim of this study is to investigate whether endplate Hounsfield ...unit (HU) values have an effect on lumbar disc degeneration (LDD) after transforaminal lumbar interbody fusion (TLIF) surgery in patients with degenerative lumbar stenosis.
Methods
This study was a retrospective analysis of patients who underwent TLIF surgery in January 2016 to October 2019. One hundred and fifty‐seven patients who underwent TLIF surgery for degenerative lumbar stenosis were enrolled in this study. Demographic data was recorded. VAS and ODI values were compared to assess the surgical outcomes in patients with or without process of LDD after TLIF surgery. Correlation analysis was performed to investigate associations between LDD and endplate HU value. Binary logistic regression analysis was carried out to study relationships between the DDD and the multiple risk factors.
Results
There was a statistically significant correlation between LDD, body mass index (BMI), age, paraspinal muscle atrophy, and total endplate scores (TEPS). Also, a strong and independent association between endplate HU value and LDD was found at every lumbar disc level (p < 0.01). After conditioning on matching factors, multivariate logistic regression analysis showed that higher endplate HU (odds ratio OR: 1.003, p = 0.003), higher TEPS (OR: 1.264, p = 0.002), higher BMI (odds ratio OR: 1.202, p = 0.002), a smaller cross‐sectional area (CSA) of the paraspinal muscle preoperatively (OR: 0.096, p < 0.001) were significant predictors of LDD development after TLIF surgery.
Conclusions
There is a significant association between LDD and endplate HU value after TLIF surgery in patients with degenerative lumbar stenosis. Beyond that, results from this study provide a mechanism by which high endplate HU value predisposes to LDD after TLIF surgery.
Measurement of the Hounsfield units (HU) values of endplate. Locating the endplate in the sagittal plane then trailing edge of hyperintense area and recording the mean HU value in the coronal plane.
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