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The degradation of cartilage in the human body is impacted by aging, disease, genetic predisposition and continued insults resulting from daily activity. The burden of cartilage defects (osteoarthritis, rheumatoid arthritis, intervertebral disc damage, knee replacement surgeries, etc.) is daunting in light of substantial economic and social stresses. This review strives to broaden the scope of regenerative medicine and tissue engineering approaches used for cartilage repair by comparing and contrasting the anatomical and functional nature of the meniscus, articular cartilage (AC) and nucleus pulposus (NP). Many review papers have provided detailed evaluations of these cartilages and cartilage-like tissues individually but none have comprehensively examined the parallels and inconsistencies in signaling, genetic expression and extracellular matrix composition between tissues. For the first time, this review outlines the importance of understanding these three tissues as unique entities, providing a comparative analysis of anatomy, ultrastructure, biochemistry and function for each tissue. This novel approach highlights the similarities and differences between tissues, progressing research toward an understanding of what defines each tissue as distinctive. The goal of this paper is to provide researchers with the fundamental knowledge to correctly engineer the meniscus, AC and NP without inadvertently developing the wrong tissue function or biochemistry.

Lumbar intervertebral disc degeneration (LIDD) serves as a principal contributor to low back pain, a condition that poses considerable global health and socioeconomic challenges. Recent studies have emphasized the significance of ferroptosis, an iron-dependent mechanism of programmed cell death, in the degeneration of nucleus pulposus cells (NPCs). This research examines the protective role of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active metabolite of Vitamin D (VD), in LIDD through the modulation of ferroptosis. The results indicate that 1,25(OH)₂D₃ significantly inhibits ferroptosis in NPCs through the reduction of lipid peroxidation, restoration of glutathione levels, and enhancement of antioxidant defenses. 1,25(OH)₂D₃ exerts its effects by activating the VD receptor (VDR) signaling pathway, which regulates important ferroptosis-associated molecules, including glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). The findings indicate the therapeutic potential of 1,25(OH)₂D₃ in alleviating LIDD, presenting a new strategy to inhibit ferroptosis and maintain intervertebral disc function.

Intervertebral disc degeneration is highly prevalent within the elderly population and is a leading cause of chronic back pain and disability. Due to the link between disc degeneration and senescence, we explored the ability of the Dasatinib and Quercetin drug combination (D + Q) to prevent an age-dependent progression of disc degeneration in mice. We treated C57BL/6 mice beginning at 6, 14, and 18 months of age, and analyzed them at 23 months of age. Interestingly, 6- and 14-month D + Q cohorts show lower incidences of degeneration, and the treatment results in a significant decrease in senescence markers p16 INK4a , p19 ARF , and SASP molecules IL-6 and MMP13. Treatment also preserves cell viability, phenotype, and matrix content. Although transcriptomic analysis shows disc compartment-specific effects of the treatment, cell death and cytokine response pathways are commonly modulated across tissue types. Results suggest that senolytics may provide an attractive strategy to mitigating age-dependent disc degeneration. Intervertebral disc degeneration is a leading cause of chronic back pain and disability. Here the authors show that long term treatment with senolytic compounds Dasatinib and Quercetin reduces disc senescence burden and ameliorates age-dependent degeneration in mice.

Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of protein-coding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.

Objective Lactate accumulation is an important factor in the intervertebral disc degeneration (IVDD). Currently, the effect and underlying mechanism of action of lactate on nucleus pulposus (NP) cell inflammation during IVDD are unclear. Previous studies have found that the NLRP3 inflammasome plays an important role in the regulation of NP inflammation. This study focused on the regulation of acid‐sensitive ion channels (ASICs) in relation to inflammation and the effect of NLRP3 on pyroptosis levels in NP cells under acidic conditions. Design For the in vitro experiments, human NP cells were exposed to 6 mM lactate solution; different groups were either treated with NLRP3 inhibitor or transfected with siRNA against NLRP3, siRNA against ASC or a mix of these, and mRNA and protein expression levels were then assessed. For the in vivo experiment, varying concentrations of lactate were injected into rat intervertebral discs and examined via magnetic resonance imaging (MRI) and histological staining. Results Extracellular lactate promoted NLRP3 inflammasome activation and degeneration of the NP extracellular matrix; furthermore, it increased the levels of inflammation and pyroptosis in the NP. Lactate‐induced NLRP3 inflammasome activation was blocked by ASIC inhibitors and NLRP3 siRNA. Conclusions Extracellular lactate regulates levels of intercellular reactive oxygen species (ROS) through ASIC1 and ASIC3. ROS activate the NF‐κB signalling pathway, thus promoting NLRP3 inflammasome activation and IL‐1β release, both of which promote NP degeneration. Schematic Illustration of NLRP3 Inflammasome Activation and Pyroptosis in Lactate‐stimulated Human NP Cells. Extracellular lactate induces Ca2+ influx by stimulating ASIC1a and ASIC3 on the cell membrane. As a second messenger, Ca2+ promotes an increase in intracellular ROS. ROS increases NLRP3 inflammasome component expression through the NF‐κB signaling pathway. NLRP3 components assemble and activate in the cells, leading to IL‐1β release and pyroptosis.

Exosome therapy is a promising therapeutic approach for intervertebral disc degeneration (IVDD) and achieves its therapeutic effects by regulating metabolic disorders, the microenvironment and cell homeostasis with the sustained release of microRNAs, proteins, and transcription factors. However, the rapid clearance and disruption of exosomes are the two major challenges for the application of exosome therapy in IVDD. Herein, a thermosensitive acellular extracellular matrix (ECM) hydrogel coupled with adipose-derived mesenchymal stem cell (ADSC) exosomes (dECM@exo) that inherits the superior properties of nucleus pulposus tissue and ADSCs was fabricated to ameliorate IVDD. This thermosensitive dECM@exo hydrogel system can provide not only in situ gelation to replenish ECM leakage in nucleus pulposus cells (NPCs) but also an environment for the growth of NPCs. In addition, sustained release of ADSC-derived exosomes from this system regulates matrix synthesis and degradation by regulating matrix metalloproteinases (MMPs) and inhibits pyroptosis by mitigating the inflammatory response in vitro. Animal results demonstrated that the dECM@exo hydrogel system maintained early IVD microenvironment homeostasis and ameliorated IVDD. This functional system can serve as a powerful platform for IVD drug delivery and biotherapy and an alternative therapy for IVDD.

Naringenin (NAR), a natural flavonoid, exerts anti-inflammatory and antioxidant pharmacology. However, the pharmacological mechanisms through which NAR prevents and treats intervertebral disc degeneration (IDD) remain unclear. We utilized bioinformatics, machine learning, and network pharmacology to identify shared targets among NAR, senescence, and IDD. Subsequently, molecular docking was conducted to evaluate NAR’s binding affinity to common target. Additionally, we used IL-1β to induce senescence and degeneration in nucleus pulposus cells (NPCs) and conducted a series of cellular assays, including immunoblotting, immunofluorescence, β-galactosidase staining, cell proliferation, cell cycle analysis, and measurement of reactive oxygen species levels, to investigate NAR’s impact on IL-1β-induced senescence and degeneration of NPCs. Our study revealed that Insulin-like growth factor binding protein 3 (IGFBP3) was the only common target. IGFBP3 exhibited significant differences between the IDD and healthy groups and proved to be an effective diagnostic marker for IDD. Molecular docking confirmed the binding between NAR and IGFBP3. In vitro experiments, we observed that Igfbp3 expression increased in the senescence and degeneration groups. Igfbp3 knockdown and NAR attenuated IL-1β-induced senescence and degenerative phenotypes in NPCs. In contrast, the effect of NAR was attenuated by recombinant IGFBP3 protein. In conclusion, our findings suggest that NAR plays a preventive and therapeutic role in IDD, likely achieved through the inhibition of Igfbp3 expression.

This study aimed to elucidate the cellular and molecular mechanisms of GSDME in GSDMD independent nucleus pulposus (NP) cell pyroptosis. We analyzed microarray datasets to identify differentially expressed genes (DEGs) in the progression of intervertebral disc degeneration (IDD) and conducted Gene Ontology analysis to elucidate DEGs-participated biological processes. We utilized lipopolysaccharides (LPS) to treat human primary NP cells to establish pyroptosis cell model. And siRNA was used to simulate a GSDMD-deficient environment. We used several regulators to figure out how GSDME was participate in pyroptosis via a GSDMD independent pathway. The molecular docking was conducted to identify compound that could possibly bind to GSDME and suppress its cleavage. Finally, Ocifisertib was intraperitoneally administered into IDD rat model to explore its therapeutic potential. Pyroptosis was activated in IDD. In vitro, LPS induced NP cell pyroptosis by promoting the cleavage of GSDMD and GSDME. In the absence of GSDMD, the cleavage of GSDME compensatively upregulated to mediate pyroptosis. Ocifisertib alleviated pyroptosis-mediated IDD by inhibiting GSDME cleavage in annulus fibrosus puncture-induced IDD rat model. Our study provides evidence that the cleavage of GSDME aggravates IDD by accelerating NP cell pyroptosis and demonstrates that Ocifisertib has therapeutic potential in IDD treatment.

Intervertebral disc degeneration (IDD) is a complicated disease in patients. The pathogenesis of IDD encompasses cellular oxidative stress, mitochondrion dysfunction and apoptosis. Melatonin eliminates oxygen free radicals, regulates mitochondrial homoeostasis and function, stimulates mitophagy and protects against cellular apoptosis. Therefore, we hypothesize that melatonin has beneficial effect on IDD by mitophagy stimulation and inhibition of apoptosis. The effects of melatonin on IDD were investigated in vitro and in vivo. For the former, melatonin diminished cellular apoptosis caused by tert‐butyl hydroperoxide in nucleus pulposus (NP) cells. Mitophagy, as well as its upstream regulator Parkin, was activated by melatonin in both a dose and time‐dependent manner. Mitophagy inhibition by cyclosporine A (CsA) partially eliminated the protective effects of melatonin against NP cell apoptosis, suggesting that mitophagy is involved in the protective effect of melatonin on IDD. In addition, melatonin was demonstrated to preserve the extracellular matrix (ECM) content of Collagen II, Aggrecan and Sox‐9, while inhibiting the expression of matrix degeneration enzymes, including MMP‐13 and ADAMTS‐5. In vivo, our results demonstrated that melatonin treatment ameliorated IDD in a puncture‐induced rat model. To conclude, our results suggested that melatonin protected NP cells against apoptosis via mitophagy induction and ameliorated disc degeneration, providing the potential therapy for IDD.

The accumulation of metabolites in the intervertebral disc is considered an important cause of intervertebral disc degeneration (IVDD). Lactic acid, which is a metabolite that is produced by cellular anaerobic glycolysis, has been proven to be closely associated with IVDD. However, little is known about the role of lactic acid in nucleus pulposus cells (NPCs) senescence and oxidative stress. The aim of this study was to investigate the effect of lactic acid on NPCs senescence and oxidative stress as well as the underlying mechanism. A puncture-induced disc degeneration (PIDD) model was established in rats. Metabolomics analysis revealed that lactic acid levels were significantly increased in degenerated intervertebral discs. Elimination of excessive lactic acid using a lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentrations of lactic acid could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing results and bioinformatic analysis demonstrated that the induction of NPCs senescence and oxidative stress by lactic acid may be related to the PI3K/Akt signaling pathway. Further study verified that high concentrations of lactic acid could induce NPCs senescence and oxidative stress by interacting with Akt and regulating its downstream Akt/p21/p27/cyclin D1 and Akt/Nrf2/HO-1 pathways. Utilizing molecular docking, site-directed mutation and microscale thermophoresis assays, we found that lactic acid could regulate Akt kinase activity by binding to the Lys39 and Leu52 residues in the PH domain of Akt. These results highlight the involvement of lactic acid in NPCs senescence and oxidative stress, and lactic acid may become a novel potential therapeutic target for the treatment of IVDD.