Biomaterials Science
·
2023
·Vol. 11
·期 10
·3629-3644
·
IF 6.6
Huitong Luo,Zetao Wang,Zhichao He,Zemin Ling,Hao Wang,Jiayi Zhu,Jingjun Nie,Dafu Chen,Qi Feng,Xiaodong Cao
Overactive inflammatory cascade accompanied by oxidative stress in the nucleus pulposus exacerbates intervertebral disc degeneration (IVDD). Hydrogels have been demonstrated to be promising in treating IVDD, yet they remain less efficacious in the case of anti-inflammation associated with antioxidation. In this study, we designed an injectable self-antioxidant hydrogel (HA/CS) with enhanced inflammation inhibitory performance for delivering chondroitin sulfate (CS) with well-documented anti-inflammatory property to treat IVDD. The hydrogel was rapidly formed via dynamic boronate ester bonding between furan/phenylboronic acid and furan/dopamine-modified hyaluronic acid (HA), and mechanically enhanced by Diels–Alder reaction-induced secondary crosslinking, partial dopamine groups of which contribute to grafting phenylboronic acid-modified CS (CS-PBA). This hydrogel exhibits favorable injectability, mechanical property, and pH-responsive delivery behavior. The dopamine moiety endows the hydrogel with efficient antioxidative property. By sustained delivery of CS, the HA/CS hydrogel is well competent to inhibit inflammatory cytokine expression and maintain anabolic/catabolic balance in an inflammation-simulated environment. Most importantly, the HA/CS hydrogel significantly ameliorates degeneration in a puncture-induced IVDD rat model. The self-antioxidant HA/CS hydrogel designed in this work may serve as a novel and promising therapeutic platform for IVDD.
研究领域:
生物材料
·
组织工程
·
骨科
·
炎症
·
氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2026
·
IF 7.5
Weiqi Zhang,Han Yin,Chenchen Wang,Xiaowei Ma,Dazhuang Miao,Guimiao Li,Wei Chen,Zhiyong Hou,Xianda Gao,Yingze Zhang,Di Zhang
Oxidative stress and apoptosis mediated senescence of nucleus pulposus cells (NPCs) and the degradation of extracellular matrix (ECM), which represent a key mechanism underlying intervertebral disc degeneration (IVDD). Mesenchymal stem cell-derived exosomes hold therapeutic potential for tissue repair; however, their clinical application is limited by rapid clearance, short half-life, and poor target specificity. To overcome these challenges, this study developed poly(lactic-co-glycolic acid) (PLGA) microspheres as a sustained-release carrier for exosomes derived under either normoxic (Exos, 21% O₂) or hypoxic (H-Exos, 1% O₂) conditions. The PLGA microspheres demonstrated high exosome-loading efficiency and provided controlled release for over four weeks. Released hypoxic exosomes activate PPAR-γ pathway, exerting better effects by reducing NPCs SA-β-gal positive rate by 59.8% and elevates Col II and ACAN levels by 30.7% and 25.5%. Animal experiments confirmed that this system effectively attenuated IVDD progression indicating its potential for clinical translation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·
IF 6.1
Wenbin Hua,Lin Xie,Chenpeng Dong,Guoyu Yang,Shouyuan Chi,Zhiqiang Xu,Cao Yang,Huiwen Wang,Xinghuo Wu
Intervertebral disc degeneration (IVDD) is a common cause of low back pain. Procyanidin C1 (PCC1) has been demonstrated to exert a protective effect on nucleus pulposus (NP) cells, and therefore, plays a critical role in the prevention and therapy of IVDD. Clarifying the pathophysiological characteristics and molecular mechanisms of IVDD may be helpful in establishing novel preventive and therapeutic strategies. This study aimed to investigate the probable mechanisms underlying the protection against acidic pH stress induced human NP cell injury. In vitro, acidic pH stress induced degeneration, mitochondrial dynamics imbalance, mitophagy, and mitochondria-mediated apoptosis in NP cells, all of which were ameliorated by PCC1. Autophagy inhibition partially eliminated the protective effects of PCC1 on mitochondrial homeostasis in NP cells. Moreover, PCC1 activated the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3) signaling pathway, a pivotal signaling pathway involved in the regulation of mitochondrial homeostasis in NP cells. In vivo, PCC1 ameliorated IVDD in a rat model and preserved the extracellular matrix of NP cells. Consequently, the protective effects of PCC1 on NP cells may inhibit IVDD progression via regulation of the SIRT3/FOXO3 signaling pathway. Therefore, regulation of the SIRT3/FOXO3 signaling pathway may be a novel preventive and therapeutic strategy for IVDD.
研究领域:
骨科学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2022
·
IF 4.145
Runze Zhao,Li Yang,Shuangjian He,Tingting Xia
Intervertebral disc degeneration (IVDD) is a main contributor to induce low back pain, and the pathogenic mechanism of IVDD remains unclear. The nucleus pulposus (NP) is a component of the intervertebral disc (IVD) that provides protection from mechanical stimuli. The matrix stiffness of NP tissue increases during the process of disc degeneration. Although several studies have found that pathological mechanical stimuli induce NP cell senescence, which is relevant for NP degeneration, however, the effect of matrix stiffness on NP cell senescence is not clear. Therefore, in the present study, we used polyvinyl alcohol (PVA) hydrogel with controllable stiffness to mimic the matrix stiffness of normal (4 kPa) and severely degenerated (20 kPa) NP tissue. Rat NP cells were isolated and cultured on substrates with different stiffness, and the cell proliferation , SA-β-gal activity, cell cycle, telomerase activity and the phenotype markers of NP cells were analyzed. Moreover, cytoskeleton staining and NP cellular Young's modulus on different substrates were also measured. To further investigate how substrate stiffness affects NP cell senescence, lysyl oxidase (LOX) was used to restore the extracellular matrix (ECM) synthesis of NP cells. The expression levels of integrin β1 and p38 MAPK were then measured. Our results showed that the 20 kPa substrate significantly induced NP cell senescence compared to the 4 kPa substrate. NP cells cultured on the 20 kPa substrate failed to maintain the expression of their phenotype markers. Furthermore, the 20 kPa substrate induced an increase of Young's modulus of NP cells, which possibly through up regulating the expressions of integrin β1 and p38 MAPK. These results indicated that the integrin β1-p38 MAPK signaling pathway may participated in substrate stiffness induced senescence of NP cells. LOX significantly increased ECM synthesis and inhibited substrate stiffness induced NP cell senescence, which indicated that matrix mechanics may be essential for maintaining the function of NP cell. Our results may provide a new perspective on the mechanism of IVDD by pathological matrix mechanics.
研究领域:
骨科
·
细胞生物学
·
生物力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yang Zhang,Deguo Xing,Yi Liu,Shiyu Sha,Yueying Xiao,Zhonghao Liu,Qingfeng Yin,Zengxin Gao,Wenguang Liu
Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with a complex pathophysiological mechanism. Increasing evidence suggests that the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a crucial role in the pathological progression of IVDD. Pyroptosis is a novel form of programmed cell death characterized by the formation of plasma membrane pores by gasdermin family proteins, leading to cell swelling, membrane rupture, and the release of inflammatory cytokines, which trigger an inflammatory response. The close relationship between pyroptosis and mitophagy has been previously described in various diseases, but the crosstalk between pyroptosis and mitophagy in IVDD remains unexplored. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and homeostasis regulation and has been shown to promote lysosomal biogenesis and function. However, the potential role and underlying mechanisms of CREG1 in the progression of IVDD have not yet been reported. In this study, we first observed that CREG1 is downregulated following IVDD and that pyroptosis occurs. Furthermore, CREG1 knockdown inhibited NPC proliferation and exacerbated apoptosis and degeneration. Moreover, we confirmed that CREG1 knockdown induced NLRP3 activation while also leading to mitophagy inhibition and mitochondrial dysfunction in NPCs. CREG1 overexpression ameliorated LPS-induced mitophagy inhibition and mitochondrial dysfunction by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. However, these protective effects were reversed by pretreatment with the mitophagy inhibitor cyclosporin A (CsA). In a rat model of IVDD, imaging and histological assessments revealed that CREG1 overexpression effectively alleviated the progression of IVDD. Additionally, CREG1 overexpression reduced the expression of NLRP3, caspase-1, and IL-1β while increasing the expression of collagen II, PINK1 and LC3, delaying the course of IVDD. Overall, this study highlights the importance of the interplay between CREG1-mediated regulation of mitophagy and pyroptosis in the pathogenesis of IVDD, identifying CREG1 as a promising therapeutic target for IVDD treatment.
研究领域:
骨科
·
细胞生物学
·
分子生物学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Huan Wang,Yifan Ding,Wei Zhang,Kang Wei,Yaping Pei,Chenming Zou,Chong Zhang,Jiahui Ding,Huang Fang,Songwei Tan
Purpose Intervertebral disc degeneration (IVDD) is the main cause of modern low back pain, leading to high societal economic costs. To find an effective medical treatment for this disease, oxymatrine liposomes (OMT-LIP) were prepared with the pH-gradient method.Materials and Methods Nucleus pulposus (NP) cells from Sprague–Dawley rats were used for the cell experiments. Kunming mice were used for in vivo imaging. LIP were employed to deliver OMT, and the particle size, ζ-potential, morphology, in vitro stability and in vitro release characteristics were evaluated. The OMT-LIP targeting effect was measured by in vivo imaging. Cell Counting Kit-8 assays were used to detect the cytotoxicity of OMT and OMT-LIP on NP cells. Therapeutic efficacy was measured by Western blot, real-time quantitative polymerase chain reaction, and apoptosis assays. Radiologic analysis was performed to evaluate the therapeutic effects in vivo.Results Orthogonal test results revealed that the mass ratio of egg yolk phosphatidylcholine to cholesterol was the key factor to effectively trap OMT in LIP. Optimal OMT-LIP showed multivesicular structure with entrapment efficiency of 73.4 ± 4.1%, particle size of 178.1 ± 2.9 nm, and ζ-potential of –13.30 ± 2.34 mV. OMT-LIP manifested excellent stability in vitro and presented significantly longer sustained release compared to OMT solution in phosphate-buffered saline (pH 7.4). OMT-LIP conspicuously increased OMT accumulation in the degenerative disc, attenuated NP cell apoptosis, reduced the expression of matrix metalloproteinases 3/9 and interleukin-6, and decreased degradation of type II collagen. In in vivo study, X-ray demonstrated that OMT-LIP inhibited IVDD.Conclusion OMT-LIP may be a useful treatment to alleviate disc inflammation and IVDD.
研究领域:
药理学
·
骨科
·
生物医学工程
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2023
·Vol. 28
·期 1
·1-24
·
IF 8.3
Lei Ming,Lin Hui,Shi Deyao,Hong Pan,Song Hui,Herman Bomansaan,Liao Zhiwei,Yang Cao
Background Intervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression.Methods The contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells.Results HDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability.Conclusion Our results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.Graphical Abstract
研究领域:
骨科
·
分子生物学
·
治疗学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Kaiqiang Sun,Chen Yan,Xinyue Dai,Yangyang Shi,Fudong Li,Liang Chen,Jingchuan Sun,Yu Chen,Jiangang Shi
Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.
研究领域:
生物医学工程
·
纳米技术
·
骨科
·
细胞生物学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Yu Shi,Wenzhen Bu,Dongchuan Chu,Wenzheng Lin,Ke Li,Xueping Huang,Xinglong Wang,Yin Wu,Shang Wu,Dandan Li,Zhuobin Xu,Zhipeng Cao,Hao Chen,Huihui Wang
Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.
研究领域:
生物医学工程
·
组织工程
·
骨科
·
细胞生物学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOR Spine
·
2024
·Vol. 7
·期 4
·e70020
·
IF 3.4
Xiaoqiang Wang,Chao Song,Daqian Zhou,Yongliang Mei,Weiye Cai,Rui Chen,Jiale Lv,Houyin Shi,Zongchao Liu
Intervertebral disc degeneration (IVDD) stands as a prevalent chronic orthopedic ailment, profoundly impacting patients' well‐being due to incapacitating low back pain. Studies have highlighted a close correlation between IVDD and the programmed cell death of nucleus pulposus (NP) cells orchestrated by interleukin‐1 beta (IL‐1β), tumor necrosis factor‐alpha (TNF‐α), and caspase‐3 (CASP3). Puerarin, renowned for its anti‐inflammatory attributes and its influence on IL‐1β and TNF‐α, emerges as a promising candidate for IVDD treatment. However, the precise mechanism by which it regulates apoptosis via these pathways remains ambiguous. This investigation utilizes bioinformatics to unveil the molecular intricacies of puerarin‐mediated apoptosis regulation in IVDD, substantiated by preliminary in vitro experiments. Analysis exposes aberrant expression of pivotal apoptosis‐associated proteins (IL‐1β, TNF‐α, CASP3, CASP8, and BCL2) in IVDD patients, with network pharmacology indicating puerarin's potential efficacy in IVDD treatment by modulating apoptosis and cellular senescence pathways. Further experiments elucidate puerarin's capacity to stimulate NP cell proliferation while inhibiting apoptosis, potentially contributing to IVDD mitigation. Western blot and PCR outcomes reveal escalated expression of apoptosis‐related proteins (IL‐1β, TNF‐α, and CASP3) in lipopolysaccharide‐treated NPCs, ameliorated by puerarin intervention. Molecular docking simulations demonstrate favorable binding properties of puerarin with apoptotic proteins, while flow cytometry analysis indicates its ability to diminish NPC apoptosis. These discoveries imply that puerarin might alleviate NPC apoptosis by modulating key targets, thereby potentially ameliorating IVDD. In summary, this study unveils the intrinsic mechanism of puerarin in regulating NPC apoptosis to alleviate IVDD, underscoring its therapeutic promise. Network pharmacology and bioinformatics analyses suggest that puerarin may mitigate intervertebral disc degeneration (IVDD) by inhibiting nucleus pulposus (NP) cell apoptosis. This hypothesis was validated through in vitro experiments, which demonstrated that puerarin significantly reduces apoptosis in NPCs.
研究领域:
骨科
·
药理学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Yu Shi,Hanwen Li,Dongchuan Chu,Wenzheng Lin,Xinglong Wang,Yin Wu,Ke Li,Huihui Wang,Dandan Li,Zhuobin Xu,Lizeng Gao,Bin Li,Hao Chen
High levels of reactive oxygen species (ROS) lead to progressive deterioration of mitochondrial function, resulting in tissue degeneration. In this study, ROS accumulation induced nucleus pulposus cells (NPCs) senescence is observed in degenerative human and rat intervertebral disc, suggesting senescence as a new therapeutic target to reverse intervertebral disc degeneration (IVDD). By targeting this, dual-functional greigite nanozyme is successfully constructed, which shows the ability to release abundant polysulfides and presents strong superoxide dismutase and catalase activities, both of which function to scavenge ROS and maintain the tissue at physical redox level. By significantly lowering the ROS level, greigite nanozyme rescues damaged mitochondrial function in IVDD models both in vitro and in vivo, rescues NPCs from senescence and alleviated the inflammatory response. Furthermore, RNA-sequencing reveals ROS-p53-p21 axis is responsible for cellular senescence-induced IVDD. Activation of the axis abolishes greigite nanozyme rescued NPCs senescence phenotype, as well as the alleviated inflammatory response to greigite nanozyme, which confirms the role of ROS-p53-p21 axis in greigite nanozyme's function to reverse IVDD. In conclusion, this study demonstrates that ROS-induced NPCs senescence leads to IVDD and the dual-functional greigite nanozyme holds strong potential to reverse this process, providing a novel strategy for IVDD management.
研究领域:
生物医学工程
·
细胞生物学
·
组织工程
·
再生医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Yucheng Ji,Yuwei Hu,Yubo Feng,Lei Liu,Zhanyi Chen,Hongxing Shen,Yingchao Han,He Xu,Lifeng Lao
Currently, mitochondrial dysfunction caused by oxidative stress is a growing concern in degenerative diseases, notably intervertebral disc degeneration (IVDD). Dysregulation of the balance of mitochondrial quality control (MQC) has been considered the key contributor, while it’s still challenging to effectively harmonize different MQC components in a simple and biologically safe way. Hydrogen gas (H 2 ) is a promising mitochondrial therapeutic molecule due to its bio-reductivity and diffusibility across cellular membranes, yet its relationship with MQC regulation remains unknown. Herein, we propose a mitochondrial ‘Birth-Death’ coordinator achieved by an intelligent hydrogen nanogenerator (Fe@HP-OD), which can sustainably release H 2 in response to the unique microenvironment in degenerated IVDs. Both in vitro and in vivo results prove alleviation of cellular oxidative stress and restoration of nucleus pulposus cells function, thereby facilitating successful IVD regeneration. Significantly, this study for the first time proposes the mitochondrial ‘Birth-Death’ coordination mechanism: 1) attenuation of overactivated mitochondrial ‘Death’ process (UPR mt and unselective mitophagy); and 2) activation of Adenosine 5‘-monophosphate-activated protein kinase (AMPK) signaling pathway for mitochondrial ‘Birth-Death’ balance (mitochondrial biogenesis and controlled mitophagy). These pioneering findings can fill in the gaps in molecular mechanisms for H 2 regulation on MQC homeostasis, and pave the way for future strategies towards restoring equilibrium of MQC system against degenerative diseases.
研究领域:
生物医学工程
·
再生医学
·
分子生物学
·
纳米技术
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）