scholarly journals Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

Bone Research ◽  
2022 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuqiang Wang ◽  
Hangang Chen ◽  
Qiaoyan Tan ◽  
Junlan Huang ◽  
Siru Zhou ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Current Therapies ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Deficient Mice

AbstractThe intervertebral disc (IVD) is the largest avascular tissue. Hypoxia-inducible factors (HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease (DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate (EP) and annulus fibrosus (AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol (2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

scholarly journals Mesenchymal Stem Cell for Prevention and Management of Intervertebral Disc Degeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Umile Giuseppe Longo ◽  
Nicola Papapietro ◽  
Stefano Petrillo ◽  
Edoardo Franceschetti ◽  
Nicola Maffulli ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Annulus Fibrosus ◽  
Intervertebral Disc Degeneration ◽  
Surgical Intervention ◽  
Pathological Condition ◽  
Treatment Strategies ◽  
Clinical Applications ◽  
Ivd Degeneration

Intervertebral disc degeneration (IVD) is a frequent pathological condition. Conservative management often fails, and patients with IVD degeneration may require surgical intervention. Several treatment strategies have been proposed, although only surgical discectomy and arthrodesis have been proved to be predictably effective. The aim of biological strategies is to prevent and manage IVD degeneration, improve the function, the anabolic and reparative capabilities of the nucleus pulposus and annulus fibrosus cells, and inhibit matrix degradation. At present, clinical applications are still in their infancy. Further studies are required to clarify the role of mesenchymal stem cells and gene therapy for the prevention and treatment of IVD degeneration.

scholarly journals Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

2021 ◽  
Vol 22 (10) ◽  
pp. 5281
Author(s):  
Jin-Woo Kim ◽  
Neunghan Jeon ◽  
Dong-Eun Shin ◽  
So-Young Lee ◽  
Myongwhan Kim ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Structural Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Metabolic Activities ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Complex Joint

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

scholarly journals Growth Factors and Anticatabolic Substances for Prevention and Management of Intervertebral Disc Degeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Umile Giuseppe Longo ◽  
Stefano Petrillo ◽  
Edoardo Franceschetti ◽  
Nicola Maffulli ◽  
Vincenzo Denaro
Keyword(s):  
Growth Factors ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Annulus Fibrosus ◽  
Intervertebral Disc Degeneration ◽  
Surgical Intervention ◽  
Treatment Strategies ◽  
Clinical Applications ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration is frequent, appearing from the second decade of life and progressing with age. Conservative management often fails, and patients with IVD degeneration may need surgical intervention. Several treatment strategies have been proposed, although only surgical discectomy and arthrodesis have been proved to be predictably effective. Biological strategies aim to prevent and manage IVD degeneration, improving the function and anabolic and reparative capabilities of the nucleus pulposus and annulus fibrosus cells and inhibiting matrix degradation. At present, clinical applications are still in their infancy. Further studies are required to clarify the role of growth factors and anticatabolic substances for prevention and management of intervertebral disc degeneration.

scholarly journals Fexofenadine Protects Against Intervertebral Disc Degeneration Through TNF Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Kaiwen Liu ◽  
Jianlu Wei ◽  
Guohua Li ◽  
Ronghan Liu ◽  
Dawang Zhao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Pathological Process ◽  
Mechanism Study ◽  
Tnf Α ◽  
Safranin O ◽  
Factor Α ◽  
Ivd Degeneration

Objective: Fexofenadine (FFD) is an antihistamine drug with an anti-inflammatory effect. The intervertebral disc (IVD) degeneration process is involved in inflammation in which tumor necrosis factor-α (TNF-α) plays an important role. This study aims to investigate the role of FFD in the pathological process of IVD degeneration.Methods: Safranin O staining was used for the measurement of cartilageous tissue in the disc. Hematoxylin-Eosin (H&E) staining was used to determine the disc construction. A rat needle puncture model was taken advantage of to examine the role of FFD in disc degeneration in vivo. Western Blotting assay, immunochemistry, and immunoflurence staining were used for the determination of inflammatory molecules. ELISA assay was performed to detect the release of inflammatory cytokines. A real-time PCR assay was analyzed to determine the transcriptional expressions of molecules.Results: Elevated TNF-α resulted in inflammatory disc degeneration, while FFD protected against TNF-α-induced IVD degeneration. Mechanism study found FFD exhibited a disc protective effect through at least two pathways. (a) FFD inhibited TNF-α-mediated extracellular matrix (ECM) degradation and (b) FFD rescued TNF-α induced inflammation in disc degeneration. Furthermore, the present study found that FFD suppressed TNF-α mediated disc degeneration via the cPLA2/NF-κB signaling pathway.Conclusions: FFD provided another alternative for treating disc degeneration through a novel mechanism. Additionally, FFD may also be a potential target for the treatment of other inflammatory-related diseases, including IVD degeneration.

scholarly journals Role of the miR-133a-5p/FBXO6 axis in the regulation of intervertebral disc degeneration

2021 ◽  
Vol 29 ◽  
pp. 123-133
Author(s):  
Xian-Fa Du ◽  
Hai-Tao Cui ◽  
He-Hai Pan ◽  
Jun Long ◽  
Hao-Wen Cui ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration

Contrasting effects of the Toll-like receptor 4 in determining ovarian follicle endowment and fertility in female adult mice

Zygote ◽  
2021 ◽  
pp. 1-7
Author(s):  
Júlio Panzera Gonçalves ◽  
Breno Augusto Magalhães ◽  
Paulo Henrique Almeida Campos-Junior
Keyword(s):  
Ovarian Follicle ◽  
Cumulus Cells ◽  
Toll Like Receptor ◽  
Female Reproduction ◽  
Toll Like Receptor 4 ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Cumulus Oocyte Complex ◽  
Estrous Cyclicity

Abstract Toll-like receptor 4 (TLR4) is best known for its role in bacteria-produced lipopolysaccharide recognition. Regarding female reproduction, TLR4 is expressed by murine cumulus cells and participates in ovulation and in cumulus–oocyte complex (COC) expansion, maternal–fetal interaction and preterm labour. Despite these facts, the role of TLR4 in ovarian physiology is not fully understood. Therefore, the aim of the present study was to investigate the effects of TLR4 genetic ablation on mice folliculogenesis and female fertility, through analysis of reproductive crosses, ovarian responsiveness and follicular quantification in TLR4−/− (n = 94) and C57BL/6 mice [wild type (WT), n = 102]. TLR4-deficient pairs showed a reduced number of pups per litter (P = 0.037) compared with WT. TLR4−/− mice presented more primordial, primary, secondary and antral follicles (P < 0.001), however there was no difference in estrous cyclicity (P > 0.05). A lower (P = 0.006) number of COC was recovered from TLR4−/− mice oviducts after superovulation, and in heterozygous pairs, TLR4−/− females also showed a reduction in the pregnancy rate and in the number of fetuses per uterus (P = 0.007) when compared with WT. Altogether, these data suggest that TLR4 plays a role in the regulation of murine folliculogenesis and in determining ovarian endowment. TLR4 deficiency may affect ovulation and pregnancy rates, potentially decreasing fertility, therefore the potential side effects of its blockade have to be carefully investigated.

Role of autophagy in intervertebral disc degeneration

2021 ◽  
Author(s):  
Rebecca Kritschil ◽  
Melanie Scott ◽  
Gwendolyn Sowa ◽  
Nam Vo
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration
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