The role of oxidative stress in intervertebral disc degeneration: Mechanisms and therapeutic implications.

Oxidative stress is one of the main driving mechanisms of intervertebral disc degeneration(IDD). Oxidative stress has been associated with inflammation in the intervertebral disc, cellular senescence, autophagy, and epigenetics of intervertebral disc cells. It and the above pathological mechanisms are closely linked through the common hub reactive oxygen species(ROS), and promote each other in the process of disc degeneration and promote the development of the disease. This reveals the important role of oxidative stress in the process of IDD, and the importance and great potential of IDD therapy targeting oxidative stress. The efficacy of traditional therapy is unstable or cannot be maintained. In recent years, due to the rise of materials science, many bioactive functional materials have been applied in the treatment of IDD, and through the combination with traditional drugs, satisfactory efficacy has been achieved. At present, the research review of antioxidant bioactive materials in the treatment of IDD is not complete. Based on the existing studies, the mechanism of oxidative stress in IDD and the common antioxidant therapy were summarized in this paper, and the strategies based on emerging bioactive materials were reviewed.

Plant molecules reinforce bone repair: Novel insights into phenol-modified bone tissue engineering scaffolds for the treatment of bone defects.

Bone defects have become a major cause of disability and death. To overcome the limitations of natural bone implants, including donor shortages and immune rejection risks, bone tissue engineering (BTE) scaffolds have emerged as a promising therapy for bone defects. Despite possessing good biocompatibility, these metal, ceramic and polymer-based scaffolds are still challenged by the harsh conditions in bone defect sites. ROS accumulation, bacterial infection, excessive inflammation, compromised blood supply deficiency and tumor recurrence negatively impact bone tissue cells (BTCs) and hinder the osteointegration of BTE scaffolds. Phenolic compounds, derived from plants and fruits, have gained growing application in treating inflammatory, infectious and aging-related diseases due to their antioxidant ability conferred by phenolic hydroxyl groups. The prevalent interactions between phenols and functional groups also facilitate their utilization in fabricating scaffolds. Consequently, phenols are increasingly incorporated into BTE scaffolds to boost therapeutic efficacy in bone defect. This review demonstrated the effects of phenols on BTCs and bone defect microenvironment, summarized the intrinsic mechanisms, presented the advances in phenol-modified BTE scaffolds and analyzed their potential risks in practical applications. Overall, phenol-modified BTE scaffolds hold great potential for repairing bone defects, offering novel patterns for BTE scaffold construction and advancing traumatological medicine.

Hsa_circ_0001946 Ameliorates Mechanical Stress-induced Intervertebral Disk Degeneration Via Targeting miR-432-5p and SOX9.

STUDY DESIGN: Experimental analysis of circular RNA in intervertebral disk degeneration (IDD). OBJECTIVE: This study aimed to explore the roles of hsa_circ_0001946 (circ-CDR1as) in mechanical stress-induced nucleus pulposus cell injury in IDD. SUMMARY OF BACKGROUND DATA: Mechanical stress is an important pathogenic factor for IDD. Excessive compression stress leads to nucleus pulposus (NP) cell apoptosis and extracellular matrix (ECM) degradation and accelerated IDD. Circ-CDR1as is associated with various degenerative conditions, but its role in IDD is not clear. Herein, we explored the roles and mechanisms of circ-CDR1as in IDD in vitro. MATERIALS AND METHODS: An in vitro model of IDD was constructed by treating NP cells with 1.0 MPa compression stress. Quantitative real-time polymerase chain reaction assay was used for detecting the expression of circ-CDR1as and miR-432-5p. Immunofluorescent analysis was performed for MMP13 detection. Western blot assay was performed for detecting apoptosis and ECM-related protein expression. Flow cytometry analysis was used for cell apoptosis analysis. The dual-luciferase reporter was used to analyze the interaction between miR-432-5p and circ-CDR1as or SOX9. Differences in means between groups were evaluated using the Student t test or one-way analysis of variance. RESULTS: In compression-treated human NP cells, we found that circ-CDR1as was significantly downregulated. Functional experiments showed that circ-CDR1as overexpression reduced the compression-induced apoptosis and ECM degradation in NP cells. Further research indicated that circ-CDR1as could act as a molecular sponge for miR-432-5p, a miRNA that enhanced compression-induced damage of NP cells by inhibiting the expression of SOX9. The luciferase reporter experiments also showed that the mutual dialogue between circ-CDR1as and miR-432-5p regulated the expression of SOX9. CONCLUSIONS: Circ-CDR1as binds to miR-432-5p and plays a protective role in mitigating compression-induced NP cell apoptosis and ECM degradation by targeting SOX9. Circ-CDR1as may provide a novel therapeutic target for the clinical management of IDD in the future.

Emerging tissue engineering strategies for annulus fibrosus therapy.

Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. IVD herniation manifests as the nucleus pulposus (NP) protruding beyond the boundaries of the intervertebral disc due to disruption of the annulus fibrosus (AF). With a deepening understanding of the importance of the AF structure in the pathogenesis of intervertebral disc degeneration, numerous advanced therapeutic strategies for AF based on tissue engineering, cellular regeneration, and gene therapy have emerged. However, there is still no consensus concerning the optimal approach for AF regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. STATEMENT OF SIGNIFICANCE: Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. However, there is still no consensus concerning the optimal approach for annulus fibrosus (AF) regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions.

Active targeting schemes for nano-drug delivery systems in osteosarcoma therapeutics.

Osteosarcoma, the most common malignant tumor of the bone, seriously influences people's lives and increases their economic burden. Conventional chemotherapy drugs achieve limited therapeutic effects owing to poor targeting and severe systemic toxicity. Nanocarrier-based drug delivery systems can significantly enhance the utilization efficiency of chemotherapeutic drugs through targeting ligand modifications and reduce the occurrence of systemic adverse effects. A variety of ligand-modified nano-drug delivery systems have been developed for different targeting schemes. Here we review the biological characteristics and the main challenges of current drug therapy of OS, and further elaborate on different targeting schemes and ligand selection for nano-drug delivery systems of osteosarcoma, which may provide new horizons for the development of advanced targeted drug delivery systems in the future.

Therapeutic perspectives of exosomes in glucocorticoid-induced osteoarthrosis.

Exosomes are widely involved in a variety of physiological and pathological processes. These important roles are also hidden in the physiological processes related to bone. Chondrocytes, osteoblasts, synovial fibroblasts, and bone marrow mesenchymal stem cells produce and secrete exosomes, thereby affecting the biology process of target cells. Furthermore, in the primary pathogenesis of osteoarthrosis induced by steroid hormones, mainly involve glucocorticoid (GC), the exosomes have also widely participated. Therefore, exosomes may also play an important role in glucocorticoid-induced osteoarthrosis and serve as a promising treatment for early intervention of osteoarthrosis in addition to playing a regulatory role in malignant tumors. This review summarizes the previous results on this direction, systematically combs the role and therapeutic potential of exosomes in GC-induced osteoarthrosis, discusses the potential role of exosomes in the treatment and prevention of GC-induced osteoarthrosis, and reveals the current challenges we confronted.

Current Insights Into the Maintenance of Structure and Function of Intervertebral Disc: A Review of the Regulatory Role of Growth and Differentiation Factor-5.

Intervertebral disc degeneration (IDD), characterized by conversion of genotypic and phenotypic, is a major etiology of low back pain and disability. In general, this process starts with alteration of metabolic homeostasis leading to ongoing inflammatory process, extracellular matrix degradation and fibrosis, diminished tissue hydration, and impaired structural and mechanical functionality. During the past decades, extensive studies have focused on elucidating the molecular mechanisms of degeneration and shed light on the protective roles of various factors that may have the ability to halt and even reverse the IDD. Mutations of GDF-5 are associated with several human and animal diseases that are characterized by skeletal deformity such as short digits and short limbs. Growth and differentiation factor-5 (GDF-5) has been shown to be a promise biological therapy for IDD. Substantial literature has revealed that GDF-5 can decelerate the progression of IDD on the molecular, cellular, and organ level by altering prolonged imbalance between anabolism and catabolism. GDF family members are the central signaling moleculars in homeostasis of IVD and upregulation of their gene promotes the expression of healthy nucleus pulposus (NP) cell marker genes. In addition, GDF signaling is able to induce mesenchymal stem cells (MSCs) to differentiate into NPCs and mobilize resident cell populations as chemotactic signals. This review will discuss the promising critical role of GDF-5 in maintenance of structure and function of IVDs, and its therapeutic role in IDD endogenous repair.

The potential role of melatonin in retarding intervertebral disc ageing and degeneration: A systematic review.

Intervertebral disc degeneration (IDD) is a common degenerative disease of the musculoskeletal system that develops with age. It is regarded as the main cause of chronic low back pain in the elderly. IDD has various causes, including ageing, mechanical overloading, and nutritional deficiency. Melatonin is a pleiotropic indole hormone secreted by the pineal gland and plays an important role in resisting various degenerative diseases. The serum levels of melatonin decline with age and are reported to be negatively correlated with the symptomatic and histopathological scores of IDD. In vivo studies have shown that exogenous administration of melatonin could maintain the structural integrity of the intervertebral disc and inhibit the development of IDD. Mechanistically, by interacting with its membrane or intracellular receptors, melatonin can promote autophagic flux, scavenge free radicals, inhibit the release of pro-inflammatory factors, and block apoptotic pathways, thereby enhancing anti-stress abilities and matrix anabolism in different types of disc cells. Therefore, melatonin supplementation may be a promising therapeutic strategy for IDD. This review aimed to summarize the latest findings regarding the therapeutic potential of melatonin in IDD.

Strategies for Biomaterial-Based Spinal Cord Injury Repair via the TLR4-NF-κB Signaling Pathway.

The repair and motor functional recovery after spinal cord injury (SCI) has remained a clinical challenge. Injury-induced gliosis and inflammation lead to a physical barrier and an extremely inhibitory microenvironment, which in turn hinders the recovery of SCI. TLR4-NF-κB is a classic implant-related innate immunomodulation signaling pathway and part of numerous biomaterial-based treatment strategies for SCI. Numerous experimental studies have demonstrated that the regulation of TLR4-NF-κB signaling pathway plays an important role in the alleviation of inflammatory responses, the modulation of autophagy, apoptosis and ferroptosis, and the enhancement of anti-oxidative effect post-SCI. An increasing number of novel biomaterials have been fabricated as scaffolds and carriers, loaded with phytochemicals and drugs, to inhibit the progression of SCI through regulation of TLR4-NF-κB. This review summarizes the empirical strategies for the recovery after SCI through individual or composite biomaterials that mediate the TLR4-NF-κB signaling pathway.

Allicin Attenuated Advanced Oxidation Protein Product-Induced Oxidative Stress and Mitochondrial Apoptosis in Human Nucleus Pulposus Cells.

Intervertebral disc degeneration (IDD) is one of the most common chronic degenerative musculoskeletal disorders. Oxidative stress-induced apoptosis of the nucleus pulposus (NP) cells plays a key role during IDD progression. Advanced oxidation protein products (AOPP), novel biomarkers of oxidative stress, have been reported to function in various diseases due to their potential for disrupting the redox balance. The current study is aimed at investigating the function of AOPP in the oxidative stress-induced apoptosis of human NP cells and the alleviative effects of allicin during this process which was known for its antioxidant properties. AOPP were demonstrated to hamper the viability and proliferation of NP cells in a time- and concentration-dependent manner and cause cell apoptosis markedly. High levels of reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were detected in NP cells after AOPP stimulation, which resulted in depolarized mitochondrial transmembrane potential (MTP). Correspondingly, higher levels of AOPP were discovered in the human degenerative intervertebral discs (IVD). It was also found that allicin could protect NP cells against AOPP-mediated oxidative stress and mitochondrial dysfunction via suppressing the p38-MAPK pathway. These results disclosed a significant role of AOPP in the oxidative stress-induced apoptosis of NP cells, which could be involved in the primary pathogenesis of IDD. It was also revealed that allicin could be a promising therapeutic approach against AOPP-mediated oxidative stress during IDD progression.