The molecular mechanism of intervertebral disc degeneration (IVDD) remains unclear. This study aimed to investigate the role of circular RNAs (circRNAs) in the pathogenesis of IVDD. We sued nucleus pulposus (NP) tissues of patients, tert-butyl hydroperoxide (TBHP) stimulated NP cells (NPCs), and IVDD rat model to explore the interaction between circERCC2 and miR-182-5p/SIRT1 axis. The results showed that downregulation of circERCC2 increased the level of miR-182-5p and decreased the level of SIRT1 in degenerative NP tissues in vivo as well as in TBHP-stimulated NPCs in vitro. Treatment of SIRT1-si activated apoptosis and inhibited mitophagy. Moreover, miR-182-5p-si could regulate the mitophagy and the apoptosis of NPCs by targeting SIRT1. The effects of circERCC2 on NPCs and IVDD rat model were mediated by miR-182-5p/SIRT1 axis. In conclusion, this study provides the first evidence that circERCC2 could ameliorate IVDD through miR-182-5p/SIRT1 axis by activating mitophagy and inhibiting apoptosis, and suggests that circERCC2 is a potentially effective therapeutic target for IVDD.
Apoptosis and calcification of endplate chondrocytes (EPCs) can exacerbate intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes (MSC-exosomes) are reported to have the therapeutic potential in IVDD. However, the effects and related mechanisms of MSC-exosomes on EPCs are still unclear. We aimed to investigate the role of MSC-exosomes on EPCs with a tert-butyl hydroperoxide (TBHP)-induced oxidative stress cell model and IVDD rat model. First, our study revealed that TBHP could result in apoptosis and calcification of EPCs, and MSC-exosomes could inhibit the detrimental effects. We also found that these protective effects were inhibited after miroRNA (miR)-31-5p levels were downregulated in MSC-exosomes. The target relationship between miR-31-5p and ATF6 was tested. miR-31-5p negatively regulated ATF6-related endoplasmic reticulum (ER) stress and inhibited apoptosis and calcification in EPCs. Our in vivo experiments indicated that sub-endplate injection of MSC-exosomes can ameliorate IVDD; however, after miR-31-5p levels were downregulated in MSC-exosomes, these protective effects were inhibited. In conclusion, MSC-exosomes reduced apoptosis and calcification in EPCs, and the underlying mechanism may be related to miR-31-5p/ATF6/ER stress pathway regulation.
Background: The repair of large bone defects is a great challenge in clinical practice. In this study, copper-loaded-ZIF-8 nanoparticles and poly (lactide-co-glycolide) (PLGA) were combined to fabricate porous PLGA/Cu(I)@ZIF-8 scaffolds using three-dimensional printing technology for infected bone repair. Methods: The surface morphology of PLGA/Cu(I)@ZIF-8 scaffolds was investigated by transmission electron microscopy and scanning electron microscopy. The PLGA/Cu(I)@ZIF-8 scaffolds were co-cultured with bacteria to determine their antibacterial properties, and with murine mesenchymal stem cells (MSCs) to explore their biocompatibility and osteoconductive properties. The bioactivity of the PLGA/Cu(I)@ZIF-8 scaffolds was evaluated by incubating in simulated body fluid. Results: The results revealed that the PLGA/Cu(I)@ZIF-8 scaffolds had porosities of 80.04 ± 5.6% and exhibited good mechanical properties. When incubated with H 2 O 2 , Cu(I)@ZIF-8 nanoparticles resulted generated reactive oxygen species, which contributed to their antibacterial properties. The mMSCs cultured on the surface of PLGA/Cu(I)@ZIF-8 scaffolds were well-spread and adherent with a high proliferation rate, and staining with alkaline phosphatase and alizarin red was increased compared with the pure PLGA scaffolds. The mineralization assay showed an apatite-rich layer was formed on the surface of PLGA/Cu(I)@ZIF-8 scaffolds, while there was hardly any apatite on the surface of the PLGA scaffolds. Additionally, in vitro, Staphylococcus aureus cultured on the PLGA/Cu(I)@ZIF-8 scaffolds were almost all dead, while in vivo inflammatory cell infiltration and bacteria numbers were dramatically reduced in infected rats implanted with PLGA/Cu@ZIF-8 scaffolds. Conclusion: All these findings demonstrate that PLGA/Cu(I)@ZIF-8 scaffolds possess excellent antibacterial and osteoconductive properties, as well as good biocompatibility and high bioactivity. This study suggests that the PLGA/ Cu(I)@ZIF-8 scaffolds could be used as a promising biomaterial for bone tissue engineering, especially for infected bone repair.
The pathogenesis of intervertebral disc degeneration (IDD) is complex, and a better understanding of IDD pathogenesis may provide a better method for the treatment of IDD. Exosomes are 40–100 nm nanosized vesicles that are released from many cell types into the extracellular space. We speculated that exosome-transported circular RNAs (circRNAs) could regulate IDD. Exosomes from different degenerative grades were isolated and added to nucleus pulposus cells (NPCs), and indicators of proliferation and apoptosis were detected. Based on the previous circRNA microarray results, the top 10 circRNAs were selected. PCR was performed to determine the circRNA with the maximum upregulation. Competing endogenous RNA (ceRNA) analysis was carried out, and the sponged microRNA (miRNA) was identified. Further functional verification of the selected circRNA was carried out in vivo and in vitro . NPCs of different degenerative grades secreted exosomes, which could regulate IDD. circRNA_0000253 was selected as having the maximum upregulation in degenerative NPC exosomes. ceRNA analysis showed that circRNA_0000253 could adsorb miRNA-141-5p to downregulate SIRT1. circRNA_0000253 was confirmed to increase IDD by adsorbing miRNA-141-5p and downregulating SIRT1 in vivo and in vitro . Exosomal circRNA_0000253 owns the maximum upregulation in degenerative NPC exosomes and could promote IDD by adsorbing miRNA-141-5p and downregulating SIRT1.
Conventional chondrosarcoma patients with greater age, axial or craniofacial tumour location, higher grade, and larger tumor size were more likely to have metastasis at diagnosis.
Abstract.A poor nutritional supply to the cells of the avascular intervertebral discs, caused by dehydration of the extracellular matrix, is a major cause of intervertebral disc degeneration (IDD). Since hepatocyte growth factor (HGF) has been shown to exert antifibrotic effects, we hypothesized that HGF treatment may be capable of retarding IDD. The present study aimed to evaluate the efficacy of HGF treatment in retarding IDD in a rat tail model of disc degeneration. The disc degeneration models were induced by needle puncture of the rat tail discs. Four weeks following needle puncture, a triblock poly(lactide-co-glycolide)-poly(ethyleneglycol)-poly(lactide-co-glycolide; PLGA-PEG-PLGA) polymer gel loaded with HGF or the gel alone was injected into rat tail discs. The efficacy of HGF in retarding IDD was assessed by magnetic resonance imaging (MRI), histological and immunohistochemical evaluation of the type I collagen, type II collagen and bone morphogenetic protein-2 (BMP-2) expression levels. Following injection of the HGF-loaded gel into the nucleus pulposus (NP), a significant trend towards an increase in T2 signal intensity (P=0.028), type II collagen staining in the NP and the number of BMP-2-positive cells in the annulus fibrosus was observed. In addition, the results demonstrated a significant trend towards a decrease in the histological score (P=0.025) and type I collagen staining in the NP compared with segments treated with the gel alone, following the induction of disc degeneration by stab injury. Following treatment with HGF, a tendency for the level of disc height to be maintained was also observed (no statistical significance). By MRI, histological and immunohistochemical evaluation, the present study demonstrated that HGF-loaded PLGA-PEG-PLGA gel was able to retard disc degeneration when injected into the degenerative discs of rat tail models.
Treatment for spinal cord injuries (SCIs) is often ineffective because SCIs result in a loss of nerve tissue, glial scar formation, local ischemia and secondary inflammation. The current promising strategy for SCI is the combination of bioactive materials and cytokines. Bioactive materials support the injured spinal cord, stabilize the morphology, and avoid excessive inflammatory responses. Fat extract (FE) is a cell‐free liquid component containing a variety of cytokines extracted from human fat tissue using mechanical methods. In this research, a biocompatible HAMC (hyaluronan and methylcellulose) loaded with FE is used to treat a model of spinal cord contusion in mice. The composite not only inhibits death of neuro‐ and vascular cells and leads to the preservation of neural and vascular structure, but also modulates the inflammatory phenotype of macrophages in the locally injured region. Specifically, FE promotes the polarization of macrophages from an inflammatory M1 phenotype to an anti‐inflammatory M2 phenotype. During the screening of the involved pathways, it is corroborated that activation of the STAT6/Arg‐1 signaling pathway is involved in macrophage M2 polarization. In summary, FE is a promising treatment for SCI, as it is easy to obtain, nonimmunogenic, and effective.
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