The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Dong, Zhengquan; Ma, Zhou; Yang, Mei-Ju; Cong, Linlin; Zhao, Ruipeng; Cheng, Liyun; Sun, Jian; Wang, Yunfei; Yang, Rong; Wei, Xiaochun; Li, Pengcui

doi:10.2147/jir.s365545

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…Sox-9driven transactivation is epigenetically controlled by several enzymes: histone acetyltransferases, methyltransferases ESET and EZH2, and the demethylase Phf2 [42][43][44]. HDAC4, a NAD+-independent histone deacetylase, triggers Sox-9 and the hypertrophic transition, as observed by Dong Z. et al in a longitudinal study of ACAN-CreERT2-HDA4 fl/fl transgenic mice with early, age-related OA with synovitis and osteophyte formation; HDAC4 silencing resulted in a very significant increase in RunX2, Col10a1, IHH signaling and MMP-13 expression, whereas Sox-9, ACAN and Col2a1 were overtly suppressed [45]. SIRT1 and SIRT6 exert important downstream regulation: the former increases COL2A1 and ACAN expression in the healthy state, while the latter suppresses several inflammatory genes.…”

Section: Sox-9 Nf-kb and Proinflammatory Cytokines Mediate Hypertroph...mentioning

confidence: 61%

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

Horváth,

Sólyom,

Székely

et al. 2023

IJMS

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Osteoarthritis (OA) is a complex disease of whole joints with progressive cartilage matrix degradation and chondrocyte transformation. The inflammatory features of OA are reflected in increased synovial levels of IL-1β, IL-6 and VEGF, higher levels of TLR-4 binding plasma proteins and increased expression of IL-15, IL-18, IL-10 and Cox2, in cartilage. Chondrocytes in OA undergo hypertrophic and senescent transition; in these states, the expression of Sox-9, Acan and Col2a1 is suppressed, whereas the expression of RunX2, HIF-2α and MMP-13 is significantly increased. NF-kB, which triggers many pro-inflammatory cytokines, works with BMP, Wnt and HIF-2α to link hypertrophy and inflammation. Altered carbohydrate metabolism and the upregulation of GLUT-1 contribute to the formation of end-glycation products that trigger inflammation via the RAGE pathway. In addition, a glycolytic shift, increased rates of oxidative phosphorylation and mitochondrial dysfunction generate reactive oxygen species with deleterious effects. An important surveyor mechanism, the YAP/TAZ signaling system, controls chondrocyte differentiation, inhibits ageing by protecting the nuclear envelope and suppressing NF-kB, MMP-13 and aggrecanases. The inflammatory microenvironment and synthesis of key matrix components are also controlled by SIRT1 and mTORc. Senescent chondrocytes represent the functional end stage of hypertrophic differentiation and characteristically upregulate p16 and p21, but also a variety of inflammatory cytokines, chemokines and metalloproteinases, developing the senescence-associated secretory phenotype. Senolysis with dendrobin, miR29b-5p and other agents has been shown to be efficient under experimental conditions, and appears to be a promising tool for the treatment of OA, as it restores COL2A1 and aggrecan synthesis, suppressing NF-kB and destructive metalloproteinases.

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Section: Sox-9 Nf-kb and Proinflammatory Cytokines Mediate Hypertroph...mentioning

confidence: 61%

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

Horváth,

Sólyom,

Székely

et al. 2023

IJMS

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“…Studies in recent years have suggested that HDAC4 exerts a regulatory function in endplate chondrocyte degeneration and NP cell degeneration [32]. For instance, HDAC4 bolsters morphological alterations in endplate chondrocytes and augments ECM degradation and endplate cartilage degeneration [33].…”

Section: Discussionmentioning

confidence: 99%

ZIP4 upregulation aggravates nucleus pulposus cell degradation by promoting inflammation and oxidative stress by mediating the HDAC4-FoxO3a axis

Shen,

Li,

Wang

et al. 2024

Aging

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Background: Extracellular matrix metabolism dysregulation in nucleus pulposus (NP) cells represents a crucial pathophysiological feature of intervertebral disc degeneration (IDD). Our study elucidates the role and mechanism of Testis expressed 11 (TEX11, also called ZIP4) extracellular matrix degradation in the NP. Materials and methods: Interleukin-1β (IL-1β) and H2O2 were used to treat NP cells to establish an IDD cell model. Normal NP tissues and NP tissues from IDD patients were harvested. ZIP4 mRNA and protein profiles in NP cells and tissues were examined. Enzyme-linked immunosorbent assay (ELISA) confirmed the profiles of TNF-α, IL-6, MDA, and SOD in NP cells. The alterations of reactive oxygen species (ROS), lactate dehydrogenase (LDH), COX2, iNOS, MMP-3, MMP-13, collagen II, aggrecan, FoxO3a, histone deacetylase 4 (HDAC4), Sirt1 and NF-κB levels in NP cells were determined using different assays. Results: The ZIP4 profile increased in the NP tissues of IDD patients and IL-1β-or H2O2-treated NP cells. ZIP4 upregulation bolstered inflammation and oxidative stress in NP cells undergoing IL-1β treatment and exacerbated their extracellular matrix degradation, whereas ZIP4 knockdown produced the opposite outcome. Mechanistically, ZIP4 upregulated HDAC4 and enhanced NF-κB phosphorylation while repressing Sirt1 and FoxO3a phosphorylation levels. HDAC4 knockdown or Sirt1 promotion attenuated the effects mediated by ZIP4 overexpression in NP cells. Conclusions: ZIP4 upregulation aggravates the extracellular matrix (ECM) degradation of NP cells by mediating inflammation and oxidative stress through the HDAC4-FoxO3a axis.

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“…The role of IHH in cartilage biology is better researched as it is involved in chondrocyte hypertrophy during development [ 82 ]. Studies have shown that the IHH signalling is dysregulated in OA and IHH expression is elevated in OA cartilage to promote hypertrophy, apoptosis and senescence [ 83 , 84 , 85 ]. In another study, inhibition of IHH signalling by ipriflavone, a compound that inhibits the IHH pathway, led to increased chondrocyte proliferation and reduced apoptosis and cartilage degeneration [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Signatures in Cartilage Ageing and Osteoarthritis

et al. 2023

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Osteoarthritis is the most common degenerative joint disorder. MicroRNAs are gene expression regulators that act post-transcriptionally to control tissue homeostasis. Microarray analysis was undertaken in osteoarthritic intact, lesioned and young intact cartilage. Principal component analysis showed that young intact cartilage samples were clustered together; osteoarthritic samples had a wider distribution; and osteoarthritic intact samples were separated into two subgroups, osteoarthritic-Intact-1 and osteoarthritic-Intact-2. We identified 318 differentially expressed microRNAs between young intact and osteoarthritic lesioned cartilage, 477 between young intact and osteoarthritic-Intact-1 cartilage and 332 between young intact and osteoarthritic-Intact-2 cartilage samples. For a selected list of differentially expressed microRNAs, results were verified in additional cartilage samples using qPCR. Of the validated DE microRNAs, four—miR-107, miR-143-3p, miR-361-5p and miR-379-5p—were selected for further experiments in human primary chondrocytes treated with IL-1β. Expression of these microRNAs decreased in human primary chondrocytes treated with IL-1β. For miR-107 and miR-143-3p, gain- and loss-of-function approaches were undertaken and associated target genes and molecular pathways were investigated using qPCR and mass spectrometry proteomics. Analyses showed that WNT4 and IHH, predicted targets of miR-107, had increased expression in osteoarthritic cartilage compared to young intact cartilage and in primary chondrocytes treated with miR-107 inhibitor, and decreased expression in primary chondrocytes treated with miR-107 mimic, suggesting a role of miR-107 in chondrocyte survival and proliferation. In addition, we identified an association between miR-143-3p and EIF2 signalling and cell survival. Our work supports the role of miR-107 and miR-143-3p in important chondrocyte mechanisms regulating proliferation, hypertrophy and protein translation.

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The Level of Histone Deacetylase 4 is Associated with Aging Cartilage Degeneration and Chondrocyte Hypertrophy

Cited by 8 publications

References 28 publications

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

ZIP4 upregulation aggravates nucleus pulposus cell degradation by promoting inflammation and oxidative stress by mediating the HDAC4-FoxO3a axis

MicroRNA Signatures in Cartilage Ageing and Osteoarthritis

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