Chondrocyte Dysfunction Research Articles

Targeting Txnip-mediated metabolic reprogramming has therapeutic potential for osteoarthritis

Osteoarthritis (OA) inflammatory microenvironment triggered glucose metabolism and mitochondrial dysfunction in chondrocytes, leading to a shift of metabolic tendency between oxidative phosphorylation and anaerobic glycolysis. Thioredoxin-interacting protein (Txnip) increased production of reactive oxygen species (ROS), which exacerbates oxidative stress, inflammation and further accelerates cartilage degeneration and extracellular matrix (ECM) degradation. Txnip expression is also positively correlated with several critical pathological glucose and lipid metabolism processes beyond inflammation and endoplasmic reticulum stress (ERS). While the role of Txnip-mediated chondrocyte metabolic reprogramming in OA has not been explored. This study focuses on the unexplored role of Txnip-mediated chondrocyte metabolic reprogramming in chondrogenesis and ECM deposition. The study reveals that upregulated glycolysis after Txnip knockdown significantly contributes to mouse chondrogenesis and ECM deposition. Moreover, verapamil, a clinically used drug that targets Txnip, shows potential for treating mouse OA. These findings suggest that targeting Txnip-mediated metabolic reprogramming could offer a novel therapeutic strategy for OA treatment.

Engineered Drug-Amphiphile Conjugate Nanoparticles for Targeted Inhibition of AQP4-Mediated NLRP3 Inflammasome Signaling in Collagen-Induced Rheumatoid Arthritis.

Aquaporins (AQPs) are transmembrane proteins that transport water, small solutes, and molecules across cell membranes. Studies have reported the role of AQPs in the activation, migration, and proliferation of immune cells, thus modulating the pathogenesis of autoimmune disease. In joints, the enhanced AQP4 expression exaggerates pathological changes like hydrarthrosis, acidosis, and hyperosmotic stress-inducing dysfunction of the articular chondrocytes, leading to articular cartilage destruction in collagen-induced arthritis (CIA). Acetazolamide (AZM), a sulfonamide carbonic anhydrase inhibitor of AQP4, reversibly decreases water permeability through AQP4 and is a potential molecule for targeting AQP4 in the CIA. However, its low solubility and low bioavailability limit its therapeutic effectiveness. Therefore, in this study, we have synthesized a polyphenol drug (gallic acid) (GA) and an amphiphile (glycerol monostearate) (GMS) conjugate to self-assemble into nanoparticles and encapsulated with AZM. Apart from AZM, GA is known for its antioxidant and anti-inflammatory properties. Therefore, intra-articular injection of AZM@GA-GMS NPs efficiently downregulates the expression of AQP4 and associated NLRP3 inflammasome activation. Moreover, the NPs are cytocompatible and showed enzyme-responsive drug release and thus offer a promising therapeutic strategy for RA by inhibiting AQP4-mediated inflammatory pathways. This opens up an avenue for treatment for RA.

Metformin-Loaded Tannic Acid Nanoparticles Attenuate Osteoarthritis by Promoting Chondrocyte Mitochondria Homeostasis Based on Mitocytosis.

The oxidative stress microenvironment and mitochondrial dysfunction in chondrocytes are key mechanisms in the development of osteoarthritis (OA). Metformin (Met) has demonstrated multiple effects on mitochondria and is regarded as a potential therapeutic agent for OA. The low blood flow characteristics in the joint cavity make targeted local delivery of metformin crucial for its clinical application. In this study, tannic acid (TA), with its natural antioxidant and anti-inflammatory properties, was used to prepare self-assemble Met-loaded TA nanoparticles (NPs). The NPs exhibit excellent reactive oxygen scavenging capability, stability in various media, and an acid-responsive release of Met. In Vitro experiments showed that NPs possess excellent biocompatibility, effectively protecting chondrocyte viability in OA's pathological environment and preventing the senescence phenotype. In addition, NPs promoted the expression of antioxidant elements in chondrocytes, restored mitochondrial membrane potential, and enhanced mitocytosis to improve mitochondrial quality. In vivo experiments further confirmed that intra-articular injection of NPs in rats with post-traumatic OA improves cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis over 8 weeks. Tissue staining further confirmed the protective effects of NPs on chondrocyte mitochondria. Importantly, both in vivo and in vitro experiments revealed that NPs provided superior cellular protection compared to TA or Met alone. Overall, this study demonstrates that NPs effectively against OA cartilage degeneration, with the advantages of easy preparation, high efficiency, and biosafety.

The miR-6779/XIAP axis alleviates IL-1β-induced chondrocyte senescence and extracellular matrix loss in osteoarthritis.

Osteoarthritis (OA) is a long-term degenerative joint disease worsening over time. Aging and chondrocyte senescence contribute to OA progression. MicroRNAs have been confirmed to regulate different cellular processes. They contribute to OA pathology and may help to identify novel biomarkers and therapies for OA. This study used bioinformatics and experimental investigations to analyze and validate differentially expressed miRNAs in OA that might affect chondrocyte apoptosis and senescence. miR-6779 was found to be significantly down-regulated in OA. Seventy-six of the predicted and miR-6779 targeted genes and the OA-associated disease genes overlapped, and these were enriched in cell proliferation, cell apoptosis, and cell cycle. miR-6779 overexpression remarkably attenuated IL-1β effects on chondrocytes by reducing MMP3 and MMP13 levels, promoting cell apoptosis, suppressing cell senescence, and increasing caspase-3, caspase-9 and reducing P16 and P21 levels. miR-6779 targeted inhibition of X-linked inhibitor of apoptosis protein (XIAP) expression. XIAP knockdown partially improved IL-1β-induced chondrocyte senescence and dysfunction. Lastly, when co-transfected with a miR-6779 agomir, the XIAP overexpression vector partially attenuated the effects of miR-6779 overexpression on chondrocytes; miR-6779 improved IL-1β-induced senescence and dysfunction in chondrocytes through targeting XIAP. miR-6779 is down-regulated, and XIAP is up-regulated in OA cartilage and IL-1β-treated chondrocytes. miR-6779 inhibits XIAP expression, thereby promoting senescent chondrocyte cell apoptosis and reducing chondrocyte senescence and ECM loss through XIAP.

Relaxin‐2 Alleviated Ferroptosis and Inflammation in TNF‐α‐Treated Chondrocytes via Regulating the Nrf2/NF‐κB Signaling Pathway

ABSTRACTExcessive inflammatory responses and ferroptosis‐associated dysfunction of chondrocytes are significant pathological features of osteoarthritis (OA). Relaxin‐2, a well‐known hormone involved in metabolic regulation across various tissues and cells, has not been extensively studied in the context of chondrocyte dysfunction and OA. T/C‐28a2 cells were stimulated with tumor necrosis factor α (TNF‐α) (10 ng/mL) with or without recombinant human relaxin‐2 (rh relaxin‐2) (25, 50 nM) for 48 h. Various techniques, including 2′,7′‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining, real‐time PCR, western blot analysis, enzyme‐linked immunosorbent assay (ELISA), and luciferase activity assays, were employed. We discovered that exposure to TNF‐α decreased the expression of Relaxin‐2 at both the mRNA and protein levels. Further investigation revealed that treatment with rh relaxin‐2 mitigated lipid peroxidation by reducing levels of reactive oxygen species (ROS), malondialdehyde (MDA), and 4‐hydroxy‐2‐nonenal (4‐HNE), while increasing superoxide dismutase (SOD) activity and glutathione (GSH) content. Notably, rh relaxin‐2 restored iron metabolism balance disrupted by TNF‐α in human T/C‐28a2 chondrocytes by decreasing Fe2+ levels, downregulating transferrin receptor 1 (TFR1) gene expression, and upregulating ferritin gene expression. Additionally, rh relaxin‐2 alleviated ferroptosis induced by TNF‐α in these cells by increasing glutathione peroxidase 4 (GPX4) expression, decreasing acyl‐CoA synthetase long‐chain family member 4 (ACSL4) expression, and reducing lactate dehydrogenase (LDH) release. Rh relaxin‐2 also inhibited the TNF‐α‐induced expression of pro‐inflammatory cytokines, interleukin‐1β (IL‐1β) and interleukin‐6 (IL‐6). Interestingly, rh relaxin‐2 attenuated TNF‐α‐induced chondrocyte degeneration by suppressing matrix metalloproteinase‐13 (MMP‐13) expression and preventing degradation of collagen type II alpha1 chain (Col2α). Mechanistically, these effects of rh relaxin‐2 were found to be mediated through the nuclear factor erythroid 2‐related factor 2 (Nrf2)/NF‐κB signaling pathway. Our findings suggest that rh relaxin‐2 could be a potential therapeutic strategy for OA.

In Vivo and In Vitro Evaluation of the Feasibility and Safety Profiles of Intraarticular Transplantation of Mitochondria for Future Use as a Therapy for Osteoarthritis.

Osteoarthritis (OA) is the most common rheumatologic disease and a major cause of pain and disability in older adults. No efficient treatment is currently available. Mitochondrial dysfunction in chondrocytes drives molecular dysregulation in OA pathogenesis. Recently, mitochondrial transfer to chondrocytes had been described, enabling transplant of mitochondria as a new avenue to modify the OA process, although evidence on its feasibility and safety remains limited.The primary objective of this study was to demonstrate the feasibility and safety of intra-articular mitochondrial transplantation. Mitochondria were isolated from liver using the procedure described by Preble and coworkers combined with magnetic beads coupled to anti-TOM22 antibodies. The organelles obtained were analyzed to determine their purity and viability. The safety and viability of the administration of the isolated mitochondria into articular tissues as well as the integration and distribution of the transplanted mitochondria within joint tissues were analyzed using both in vitro and in vivo models. We established an efficient, reproducible, effective, and rapid protocol for isolating mitochondria from liver. We obtained mitochondria with high viability, yield, and purity. The isolated mitochondria were injected into joint tissue using both in vitro and in vivo models. Functional mitochondria were detected in the extracellular matrix of the cartilage, menisci and synovium. Our results establish a safe and viable protocol for mitochondrial isolation and intra-articular injection. The methodology and findings presented here pave the way for future studies in osteoarthritis models to validate mitochondrial transplantation as a potentially effective treatment for OA.

KLF9-GRK5-HDAC6 axis aggravates osteoarthritis pathogenesis by promoting chondrocyte extracellular matrix degradation and apoptosis

Osteoarthritis (OA) is a degenerative joint disease that affects the cartilage and surrounding tissues. The transcription factor Kruppel-like family factor 9 (KLF9) has been identified as a regulator of tumorigenesis. However, its role in OA is still not fully understood. Herein, this study aimed to access the potential role and molecular mechanism by which KLF9 regulates OA development. KLF9 was upregulated in cartilage tissues of OA patients and medial meniscotibial ligament (MMTL)-induced OA rats, as well as in IL-1β-treated chondrocytes. Furthermore, knockdown of KLF9 inhibited OA-related cartilage injury, as evidenced by inhibiting chondrocyte extracellular matrix (ECM) degradation, increasing chondrocyte viability, and decreasing apoptosis. Conversely, overexpression of KLF9 had the opposite effect. The downstream mechanism of KLF9 was confirmed. KLF9 mediated the transcription of G protein-coupled receptor kinase 5 (GRK5) by directly targeting the GRK5 promoter. GRK5 knockdown eliminated the effects of KLF9 overexpression on chondrocyte dysfunction. It was also found that GRK5 combined with histone deacetylase 6 (HDAC6) and promoted HDAC6 phosphorylation. The use of the HDAC6 inhibitor TubastatinA also abolished the effects of GRK5 overexpression on chondrocyte ECM degradation and apoptosis. These results demonstrate that the KLF9-GRK5-HDAC6 axis plays a crucial role in promoting the progression of OA.

Safety and efficacy of mesenchymal stromal cells mitochondria transplantation as a cell-free therapy for osteoarthritis

ObjectiveThe inflammatory responses from synovial fibroblasts and macrophages and the mitochondrial dysfunction in chondrocytes lead to oxidative stress, disrupt extracellular matrix (ECM) homeostasis, and accelerate the deterioration process of articular cartilage in osteoarthritis (OA). In recent years, it has been proposed that mesenchymal stromal cells (MSC) transfer their functional mitochondria to damaged cells in response to cellular stress, becoming one of the mechanisms underpinning their therapeutic effects. Therefore, we hypothesize that a novel cell-free treatment for OA could involve direct mitochondria transplantation, restoring both cellular and mitochondrial homeostasis.MethodsMitochondria were isolated from Umbilical Cord (UC)-MSC (Mito-MSC) and characterized based on their morphology, phenotype, functions, and their ability to be internalized by different articular cells. Furthermore, the transcriptional changes following mitochondrial uptake by chondrocytes were evaluated using an Affymetrix analysis, Lastly, the dose dependence therapeutic efficacy, biodistribution and immunogenicity of Mito-MSC were assessed in vivo, through an intra-articular injection in male C57BL6 mice in a collagenase-induced OA (CIOA) model.ResultsOur findings demonstrate the functional integrity of Mito-MSC and their ability to be efficiently transferred into chondrocytes, synovial macrophages, and synovial fibroblasts. Moreover, the transcriptomic analysis showed the upregulation of genes involved in stress such as DNA reparative machinery and inflammatory antiviral responses. Finally, Mito-MSC transplantation yielded significant reductions in joint mineralization, a hallmark of OA progression, as well as improvements in OA-related histological signs, with the lower dose exhibiting better therapeutic efficacy. Furthermore, Mito-MSC was detected within the knee joint for up to 24 h post-injection without eliciting an inflammatory response in CIOA mice.ConclusionCollectively, our results reveal that mitochondria derived from MSC are transferred to key articular cells and are retained in the joint without generating an inflammatory immune response mitigating articular cartilage degradation in OA, probably through a restorative effect triggered by the stress antiviral response within OA chondrocytes.

Single-Cell RNA sequencing reveals mitochondrial dysfunction in microtia chondrocytes

Microtia is a congenital malformation characterized by underdevelopment of the external ear. While chondrocyte dysfunction has been implicated in microtia, the specific cellular abnormalities remain poorly understood. This study aimed to investigate mitochondrial dysfunction in microtia chondrocytes using single-cell RNA sequencing. Cartilage samples were obtained from patients with unilateral, non-syndromic microtia and healthy controls. Single-cell RNA sequencing was performed using the 10 × Genomics platform. Bioinformatic analyses including cell type identification, trajectory analysis, and gene co-expression network analysis were conducted. Mitochondrial function was assessed through ROS levels, membrane potential, and transmission electron microscopy. Chondrocytes from microtia samples showed lower mitochondrial function scores compared to normal samples. Trajectory analysis revealed more disorganized differentiation patterns in microtia chondrocytes. Mitochondrial dysfunction in microtia chondrocytes was confirmed by increased ROS production, decreased membrane potential, and altered mitochondrial structure. Gene co-expression network analysis identified hub genes associated with mitochondrial function, including SDHA, SIRT1, and PGC1A, which showed reduced expression in microtia chondrocytes. This study provides evidence of mitochondrial dysfunction in microtia chondrocytes and identifies potential key genes involved in this process. These findings offer new insights into the pathogenesis of microtia and may guide future therapeutic strategies.

Nanoengineered cargo with targeted invivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis.

Nanoengineered cargo with targeted invivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis.

Circ-PDE1C/miR-766-3p/SGTB axis regulates the IL-1β-induced apoptosis, inflammation and oxidative stress in human chondrocytes

Abstract Background Osteoarthritis (OA) is a common degenerative joint disease. Circular RNA Phosphodiesterase 1 C (circ-PDE1C, hsa_circ_0134111) has participated in the IL-1β-induced chondrocyte damages. The objective of our study was to explore the molecular mechanism of circ-PDE1C. Methods Circ-PDE1C, microRNA-766-3p (miR-766-3p) or Small Glutamine Rich Tetratricopeptide Repeat Co-Chaperone Beta (SGTB) expression was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK-8) assay and flow cytometry were used to analyze proliferation and apoptosis, respectively. Western blotting assay was performed for protein detection. The inflammatory cytokines were measured by Enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by commercial kits. Target analysis was conducted by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Results Circ-PDE1C was abnormally overexpressed in OA tissues and IL-1β-exposed chondrocytes. Downregulation of circ-PDE1C alleviated the IL-1β-induced cell apoptosis, inflammation, extracellular matrix degradation and oxidative stress. Circ-PDE1C could interact with miR-766-3p to serve as miRNA sponge. The function of si-circ-PDE1C was attributed to the inhibition of miR-766-3p. Additionally, miR-766-3p directly targeted the 3’UTR of SGTB. The miR-766-3p upregulation impeded the IL-1β-triggered cell damages through reducing the level of SGTB. Moreover, SGTB expression was regulated by circ-PDE1C via binding to miR-766-3p in IL-1β-induced chondrocytes. Conclusion Altogether, circ-PDE1C enhanced the IL-1β-induced dysfunction in chondrocytes via upregulating SGTB by targeting miR-766-3p.

Extracellular Vesicles Derived Ectonucleoside Triphosphate Diphosphohydrolase 3 Alleviates Mitochondrial Dysfunction of Osteoarthritis Chondrocytes via Ectonucleotide Pyrophosphatase/Phosphodiesterase 1-Induced Suppression of the AKT/Notch2 Pathway.

Osteoarthritis (OA) is the most common joint disease that usually starts from joint cartilage injury. Notch2, a versatile signaling in human development and diseases, was recently uncovered to be an important regulator in chondrocyte damage. However, in OA chondrocytes, how Notch2 activation is dysregulated is largely unknown. Here, integrated bioinformatic analysis was performed on GEO datasets (GSE199193 and GSE224255) to search potential extracellular vesicles (EVs) derived regulators of Notch2 in OA chondrocytes. Ectonucleoside triphosphate diphosphohydrolase 3 (Entpd3), a most differentially expressed gene both in LPS-induced macrophage EV and Notch2 mutant chondrocytes, was screened as the candidate regulator of Notch2 in OA chondrocytes. Gain-of-function experiments in cultured human chondrocytes revealed that recombinant Entpd3 protein and macrophage EV both had a protective effect on LPS-induced inflammation, oxidative stress, apoptosis, and collagen loss in chondrocytes. In terms of mechanism, Entpd3 directly interacted with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and suppressed AKT/Notch2-mediated mitochondrial dysfunction. Finally, we verified that either macrophage EV administration or Entpd3 overexpression was able to alleviate osteoarthritis in mice in vivo. In conclusion, Entpd3 is identified as a new regulator in OA, which alleviates mitochondrial dysfunction induced chondrocyte damage via ENPP1-induced suppression of the AKT/Notch2 pathway.

The role of lncRNA TSIX in osteoarthritis pathogenesis: mechanistic insights and clinical biomarker potential

BackgroundThis study seeks to elucidate the expressions of lncRNA TSIX in Osteoarthritis (OA) and to explore its mechanisms in regulating OA progression.MethodsRT-qPCR was employed to analyze the expression of TSIX in OA patients classified by Kellgren-Lawrence (K-L) grades. Receiver operator characteristic (ROC) was conducted to evaluate the diagnostic value of TSIX. Correlation between TSIX levels and clinical scores such as Lysholm and visual analogue scale (VAS) score was evaluated using Pearson method. IL-1β-induced SW1353 cells served as an in vitro model. The cell function were assessed by flow cytometry and cell counting kit-8 (CCK-8) assay. The relationship between TSIX and miR-320a was verified by luciferase reporting system, while bioinformatics approaches were utilized to predict the downstream target genes of miR-320a.ResultsThe findings revealed that TSIX level in OA patients was elevated compared to that of the control group, with a notable progressive increase in TSIX expression correlated with higher K-L grades. In OA patients, the Lysholm score showed a negative correlation with TSIX expression, while the VAS score displayed a positive correlation with TSIX levels. Cell studies demonstrated that inhibition of TSIX enhanced cell viability and mitigated IL-1β-induced apoptosis by targeting miR-320a, in addition to promoting Aggrecan and Collagen II secretion. Luciferase reporter assay further validated the targeting interaction among TSIX, miR-320a, and PTEN.ConclusionsThis study demonstrated an increased expression of TSIX in OA patients. It suggests that TSIX may play a role in chondrocyte dysfunction during OA by modulating the miR-320a/PTEN axis.

KLF2 Inhibits Ferroptosis and Improves Mitochondrial Dysfunction in Chondrocyte Through SIRT1/GPX4 Signaling to Improve Osteoarthritis.

Osteoarthritis (OA), a disease of articular joints, is the leading cause of disability in the elderly. Repressing ferroptosis and improving mitochondrial function can delay the progression of OA. Kruppel-like factor 2 (KLF2) exerts a protective effect on OA. However, whether KLF2 affects ferroptosis and mitochondrial function during OA remains unknown. The OA in vivo and in vitro models were constructed in this work. The structural damage of knee joint in OA mice was evaluated through Micro-CT scanning. H&E, SOFG, TB, and TUNEL staining were applied for pathological examination of cartilage tissues. ELISA was employed to examine the contents of inflammatory factors. Additionally, iron deposition in cartilage tissues was measured by Prussian blue staining, and the levels of proteins related to ferroptosis were assessed by immunoblotting. Besides, mitochondrial morphology and function were estimated using a transmission electron microscope and JC-1 staining. In interleukin (IL)-1β-treated C28/I2 cells, the levels of inflammatory factors, intracellular ROS, mitochondrial ROS, lipid ROS, and Fe2+ were measured. Mitochondrial function was evaluated by detecting the levels of mitochondrial membrane potential (MMP), ATP, mPTP, and OCR. KLF2 overexpression ameliorated the structural damage of knee cartilage in OA mice. KLF2 upregulation inhibited ferroptosis and alleviated mitochondrial damage in knee cartilage of OA mice and IL-1β-treated C28/I2 cells. Moreover, KLF2 overexpression activated SIRT1/GPX4 signaling in vivo and in vitro. EX527 addition blocked the influences of KLF2 upregulation on ferroptosis and mitochondrial dysfunction in IL-1β-treated C28/I2 cells. Altogether KLF2 inhibits ferroptosis and improves mitochondrial dysfunction in chondrocytes through SIRT1/GPX4 signaling to improve OA.

Melatonin Alleviates High Glucose-induced Oxidative Stress and Mitochondrial Dysfunction in Chondrocytes

Background: Hyperglycemia triggers mitochondrial dysfunction in chondrocytes, potentially contributing to cell damage and the onset of osteoarthritis. Objective: This study is undertaken with the objective of examining the protective properties of melatonin against toxicity induced by high glucose in C28I2 human chondrocytes. Methods: To determine non-cytotoxic concentrations of melatonin, various concentrations (10, 25, 50, 75, 100, 500, and 1000 μM) were assessed over different time periods (24, 48, and 72 hours) for their impact on C28I2 cell viability. Following this, cells underwent a pretreatment with melatonin (10 and 100 μM) for 6 hours. This was followed by subjecting the cells to a high concentration of glucose (75 mM) for 48 hours. Oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), alongside the enzymatic activities of glutathione peroxidase, superoxide dismutase, and catalase were quantitatively assessed. To assess mitochondrial function, we evaluated the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio and measured the mitochondrial membrane potential (MMP). Results: Elevated glucose levels significantly increased ROS and MDA levels, accompanied by reduced MMP, an elevated ADP/ATP ratio, and altered antioxidant enzyme activity. Pretreatment with melatonin effectively reversed the mitochondrial toxicity induced by high glucose (75 mM). Conclusion: These results indicate that melatonin exhibits a protective influence against hyperglycemia- induced toxicity in chondrocyte mitochondria.

The protective effects of orexin-A in alleviating cell senescence against interleukin-1β (IL-1β) in chondrocytes.

Osteoarthritis (OA) is one of the most important causes of global disability, and dysfunction of chondrocytes is an important risk factor. The treatment of OA is still a challenge. Orexin-A is a hypothalamic peptide, and its effects in OA are unknown. In this study, we found that exposure to interleukin-1β (IL-1β) reduced the expression of orexin-2R, the receptor of orexin-A in TC-28a2 chondrocytes. Importantly, the senescence-associated β-galactosidase (SA-β-gal) staining assay demonstrated that orexin-A treatment ameliorates IL-1β-induced cellular senescence. Importantly, the presence of IL-1β significantly reduced the telomerase activity of TC-28a2 chondrocytes, which was rescued by orexin-A. We also found that orexin-A prevented IL-1β-induced increase in the levels of Acetyl-p53 and the expression of p21. It is shown that orexin-A mitigates IL-1β-induced reduction of sirtuin 3 (SIRT3). Silencing of SIRT3 abolished the protective effects of orexin-A against IL-1β-induced cellular senescence. These results imply that orexin-A might serve as a promising therapeutic agent for OA.

Spinosin ameliorates osteoarthritis through enhancing the Nrf2/HO-1 signaling pathway.

Osteoarthritis (OA) is a common degenerative joint disease in the elderly, while oxidative stress-induced chondrocyte degeneration plays a key role in the pathologic progression of OA. One possible reason is that theexpression of nuclear factor erythroid 2-related factor 2 (Nrf2), which acts as the intracellular defense factor against oxidative stress, is significantly inhibited in chondrocytes. Spinosin (SPI) is a potent Nrf2 agonist, butits effect on OA is still unknown. In this study, we found that SPI can alleviate tert-Butyl hydroperoxide (TBHP)-induced extracellular matrix degradation of chondrocytes. Additionally, SPI can effectively activateNrf2, heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase 1 (NQO1) in chondrocytes under theTBHP environment. When Nrf2 was silenced by siRNA, the cartilage protective effect of SPI was also weakened.Finally, SPI showed good alleviative effects on OA in mice. Thus, SPI can ameliorate oxidative stress-induced chondrocyte dysfunction and exhibit a chondroprotective effect through activating the Nrf2/HO-1pathway, which may provide a novel and promising option for the treatment of OA.

An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment

An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment

Sakuranetin reduces inflammation and chondrocyte dysfunction in osteoarthritis by inhibiting the PI3K/AKT/NF-κB pathway

Sakuranetin reduces inflammation and chondrocyte dysfunction in osteoarthritis by inhibiting the PI3K/AKT/NF-κB pathway

T-2 toxin induces mitochondrial dysfunction in chondrocytes via the p53-cyclophilin D pathway

T-2 toxin induces mitochondrial dysfunction in chondrocytes via the p53-cyclophilin D pathway