Effects of Visfatin on Intracellular Mechanics and Catabolism in Human Primary Chondrocytes through Glycogen Synthase Kinase 3β Inactivation

Chang, Shun‐Fu; Huang, Kuo‐Chin; Lee, Kuan‐Han; Chiang, Yang‐Jen; Lee, Wei-Ru; Hsieh, Rong-Ze; Su, Yu‐Ping; Wu, Shun-Chi

doi:10.3390/ijms22158107

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…A recent study showed that the inactivation of glycogen synthase kinase 3 β (GSK3B) in human primary chondrocytes could lead to a decrease in cell elasticity and viscosity, as well as the destruction of cell microtubule networks [ 17 ]. We collected 18 cartilage tissues from amputation patients as a normal control group and 25 cartilage tissues from PTOA patients.…”

Section: Resultsmentioning

confidence: 99%

GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter

Sun

et al. 2022

Disease Markers

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Background. Glycogen synthase kinase 3β (GSK3B) is reported to be a protective factor for the degradation of chondrocytes by extracellular mechanisms. Nuclear receptor subfamily 4 group A member 3 (NR4A3) is a proinflammatory factor in osteoarthritis. Their regulation mechanism in posttraumatic osteoarthritis (PTOA) is not fully understood. Methods. GSK3B expression in the cartilage tissue of PTOA patients was analyzed by western blotting. IL-1β-induced chondrocytes were transfected with pcDNA-GSK3B, and then, the cell viability, apoptosis, expression of the chondrocyte extracellular matrix degradation-related genes MMP13, aggrecan, and type II collagen, and secretion of inflammatory factors TNF-α and IL-6 were detected. Co-IP was used to analyze the interaction between GSK3B and DNMT1. Ch-IP and methylation-specific PCR assays were used for methylation. Also, cells were transfected with pcDNA-GSK3B or together with pcDNA-NR4A3, as well as transfected with si-NR4A3, and then, cell functions were tested. Then, the mice subjected to destabilization of medial meniscus (DMM) surgery were intra-articular injected with 100 μL of the following adeno-related virus vectors (empty vector, Ad-GSK3B, scrambled shRNA, and sh-NR4A3), respectively, and the virus titer was 2 × 10 8 TU / mL . Cartilage integrity was evaluated by safranin O/fast green staining, HE staining, and Osteoarthritis Research Society International (OARSI) score. Results. The expression of GSK3B protein was downregulated in PTOA patients. GSK3B overexpression alleviated IL-1β-induced chondrocyte apoptosis and extracellular matrix degradation, as well as cartilage mineralization in PTOA model mice. NR4A3 overexpression reversed the effect of GSK3B on IL-1β-induced chondrocyte functions. GSK3B could recruit DNMT1 to the NR4A3 promoter region to promote the methylation of NR4A3 and inhibit the expression of NR4A3 protein. Similarly, NR4A3 interference alleviated cartilage degradation under stimulating conditions by inhibiting the activation of the JAK2/STAT3 signaling pathway. Conclusion. GSK3B recruits DNMT1 to the NR4A3 promoter region and inhibits the activation of the NR4A3-mediated JAK2/STAT3 signaling pathway, thereby alleviating PTOA.

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Section: Resultsmentioning

confidence: 99%

GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter

Sun

et al. 2022

Disease Markers

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“…VISFATIN increased the generation of inflammatory cytokines (such as IL-6, TNF-α, and MMPs) in human OA cartilage chondrocytes, and intra-articular injection of VISFATIN induced cartilage destruction in a mouse model ( Yang et al, 2015 ; Philp et al, 2021 ). Moreover, VISFATIN can influence intracellular mechanics and dynamic catabolism in primary chondrocytes through p38 signaling-mediated GSK3β inactivation ( Chang et al, 2021 ). However, we found that VISFATIN signaling in damaged cartilage was lower than that in intact tissue.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing analysis of human chondrocytes reveals cell–cell communication alterations mediated by interactive signaling pathways in osteoarthritis

Kang

Zhang²,

Wang

et al. 2023

Front. Cell Dev. Biol.

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Objective: Osteoarthritis (OA) is a common joint disorder characterized by degenerative articular cartilage, subchondral bone remodeling, and inflammation. Increasing evidence suggests that the substantial crosstalk between cartilage and synovium is closely related to Osteoarthritis development, but the events that cause this degeneration remain unknown. This study aimed to explore the alterations in intercellular communication involved in the pathogenesis of Osteoarthritis using bioinformatics analysis.Methods: Single-cell transcriptome sequencing (scRNA-seq) profiles derived from articular cartilage tissue of patients with Osteoarthritis were downloaded from a public database. Chondrocyte heterogeneity was assessed using computational analysis, and cell type identification and clustering analysis were performed using the “FindClusters” function in the Seurat package. Intercellular communication networks, including major signaling inputs and outputs for cells, were predicted, and analyzed using CellChat.Results: Seven molecularly defined chondrocytes clusters (homeostatic chondrocytes, hypertrophic chondrocyte (HTC), pre-HTC, regulatory chondrocytes, fibro-chondrocytes (FC), pre-FC, and reparative chondrocyte) with different compositions were identified in the damaged cartilage. Compared to those in the intact cartilage, the overall cell–cell communication frequency and communication strength were remarkably increased in the damaged cartilage. The cellular communication among chondrocyte subtypes mediated by signaling pathways, such as PTN, VISFATIN, SPP1, and TGF-β, was selectively altered in Osteoarthritis. Moreover, we verified that SPP1 pathway enrichment scores increased, but VISFATIN pathway enrichment scores decreased based on the bulk rna-seq datasets in Osteoarthritis.Conclusion: Our results revealed alterations in cell–cell communication among OA-related chondrocyte subtypes that were mediated by specific signaling pathways, which might be a crucial underlying mechanism associated with Osteoarthritis progression.

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“…From a biomechanical standpoint, visfatin disrupts microtubule and microfilament networks, influencing intracellular mechanics by decreasing intracellular elasticity and viscosity through glycogen synthase kinase 3β (GSK3β) inactivation (Chang et al, 2021). In summary, visfatin functions as a central catabolic agent in OA pathogenesis, mediating the deterioration of osteoarthritic cartilage (Yang et al, 2015).…”

Section: Visfatinmentioning

confidence: 99%

Exerkines and osteoarthritis

Jia,

Yu,

Bai

2023

Front. Physiol.

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Osteoarthritis (OA) is the most prevalent chronic joint disease, with physical exercise being a widely endorsed strategy in its management guidelines. Exerkines, defined as cytokines secreted in response to acute and chronic exercise, function through endocrine, paracrine, and/or autocrine pathways. Various tissue-specific exerkines, encompassing exercise-induced myokines (muscle), cardiokines (heart), and adipokines (adipose tissue), have been linked to exercise therapy in OA. Exerkines are derived from these kines, but unlike them, only kines regulated by exercise can be called exerkines. Some of these exerkines serve a therapeutic role in OA, such as irisin, metrnl, lactate, secreted frizzled-related protein (SFRP), neuregulin, and adiponectin. While others may exacerbate the condition, such as IL-6, IL-7, IL-15, IL-33, myostatin, fractalkine, follistatin-like 1 (FSTL1), visfatin, activin A, migration inhibitory factor (MIF), apelin and growth differentiation factor (GDF)-15. They exerts anti-/pro-apoptosis/pyroptosis/inflammation, chondrogenic differentiation and cell senescence effect in chondrocyte, synoviocyte and mesenchymal stem cell. The modulation of adipokine effects on diverse cell types within the intra-articular joint emerges as a promising avenue for future OA interventions. This paper reviews recent findings that underscore the significant role of tissue-specific exerkines in OA, delving into the underlying cellular and molecular mechanisms involved.

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Effects of Visfatin on Intracellular Mechanics and Catabolism in Human Primary Chondrocytes through Glycogen Synthase Kinase 3β Inactivation

Cited by 4 publications

References 46 publications

GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter

GSK3B Overexpression Alleviates Posttraumatic Osteoarthritis in Mice by Promoting DNMT1-Mediated Hypermethylation of NR4A3 Promoter

Single-cell RNA sequencing analysis of human chondrocytes reveals cell–cell communication alterations mediated by interactive signaling pathways in osteoarthritis

Exerkines and osteoarthritis

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