Transcription factor Krüppel-like factor 5-regulated N-myc downstream-regulated gene 2 reduces IL-1β-induced chondrocyte inflammatory injury and extracellular matrix degradation

Mei, Xiaoliang; Din, Hao; Zhao, Jianning; Tong, Jian; Zhu, Wei

doi:10.1080/21655979.2021.1971483

Cited by 7 publications

(10 citation statements)

References 35 publications

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“…Indeed, overexpression of KLF5 counteracts the effect of NDRG2 on reducing the release of inflammatory cytokines by up-regulating the expression of a large number of proinflammatory cytokines (TNFα, IL-6, p-NF-κB p65 and Cox-2). 86 Overall, the aforementioned findings provide compelling evidence that aberrant expression levels of KLF2, KLF4 and KLF5, important OA regulatory factors, can impact the inflammatory pathological state of OA. KLF5 stimulates inflammation, while KLF2 and KLF4 are negative regulatory factors in OA inflammation.…”

Section: Klfs and Inflammatory Responsementioning

confidence: 88%

“…Likewise, KLF5 is up-regulated in IL-1β-induced ATDC5 chondrocytes. 86 N-myc downstream-regulated gene 2 (NDRG2) has been identified as a key biomarker and regulator of OA. 87 Mei et al 86 reported that KLF5 overexpression increased the expression of ECM degradation-related MMP3, MMP13 and ADAMTS4 levels, decreased collagen II expression and reversed the ameliorative effect of NDRG2 on ECM degradation.…”

Section: Klfs and The Degradation Of Ecmmentioning

confidence: 99%

“…86 N-myc downstream-regulated gene 2 (NDRG2) has been identified as a key biomarker and regulator of OA. 87 Mei et al 86 reported that KLF5 overexpression increased the expression of ECM degradation-related MMP3, MMP13 and ADAMTS4 levels, decreased collagen II expression and reversed the ameliorative effect of NDRG2 on ECM degradation. KLF5 has also been proved to be involved in cartilage degeneration mediated by EGR1, promoting the expression of MMP9 and MMP13 in chondrocytes and inhibiting the expression of COl2A1.…”

Section: Klfs and The Degradation Of Ecmmentioning

confidence: 99%

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KLF transcription factors in bone diseases

Wang,

Han,

Dmitrii

et al. 2024

J Cellular Molecular Medi

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Krüppel‐like factors (KLFs) are crucial in the development of bone disease. They are a family of zinc finger transcription factors that are unusual in containing three highly conserved zinc finger structural domains interacting with DNA. It has been discovered that it engages in various cell functions, including proliferation, apoptosis, autophagy, stemness, invasion and migration, and is crucial for the development of human tissues. In recent years, the role of KLFs in bone physiology and pathology has received adequate attention. In addition to regulating the normal growth and development of the musculoskeletal system, KLFs participate in the pathological process of the bones and joints and are intimately linked to several skeletal illnesses, such as osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis (OP) and osteosarcoma (OS). Consequently, targeting KLFs has emerged as a promising therapeutic approach for an array of bone disorders. In this review, we summarize the current literature on the importance of KLFs in the emergence and regulation of bone illnesses, with a particular emphasis on the pertinent mechanisms by which KLFs regulate skeletal diseases. We also discuss the need for KLFs‐based medication‐targeted treatment. These endeavours offer new perspectives on the use of KLFs in bone disorders and provide prognostic biomarkers, therapeutic targets and possible drug candidates for bone diseases.

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Section: Klfs and Inflammatory Responsementioning

confidence: 88%

Section: Klfs and The Degradation Of Ecmmentioning

confidence: 99%

Section: Klfs and The Degradation Of Ecmmentioning

confidence: 99%

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KLF transcription factors in bone diseases

Wang,

Han,

Dmitrii

et al. 2024

J Cellular Molecular Medi

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“…The IL-1β pro-inflammatory cytokine is usually used to stimulate chondrocytes to undergo OA-like changes in vitro . NDRG2 expression is much lower in IL-1β–treated chondrocytes than in untreated cells, and its overexpression by transfection of pcDNA3.1(+)/NDRG2 restores the inflammatory response and ECM degradation in chondrocytes ( 48 ). Furthermore, NDRG2 expression level is significantly correlated with astrocyte senescence, and NDRG2 can directly interact with NF-κB and inhibit the nuclear import and DNA-binding activity of the NF-κB p65 subunit in primary astrocytes ( 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression

et al. 2023

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BackgroundOsteoarthritis (OA) is a prevalent senescence-related disease with substantial joint pain, loss of joint function, and cartilage degeneration. Because of the paucity of single-cell studies of OA and the gene dropout problem of single-cell RNA sequencing, it is difficult to acquire an in-depth understanding of the molecular characteristics of various chondrocyte clusters.MethodsHere, we aimed to provide new insights into chondrocyte senescence and a rationale for the development of effective intervention strategies for OA by using published single-cell RNA-sequencing data sets and the metaVIPER algorithm (Virtual Inference of Protein activity by Enriched Regulon). This algorithm was employed to present a proteome catalog of 62,449 chondrocytes from the cartilage of healthy individuals and OA patients at single-cell resolution. Furthermore, histopathologic analysis was carried out in cartilage samples from clinical patients and experimental mouse models of OA to validate above results.ResultsWe identified 16 protein-activity-based chondrocyte clusters as well as the underlying master regulators in each cluster. By assessing the enrichment score of each cluster in bulk RNA-sequencing data, followed by gene-set variation analysis, we preliminarily identified a novel subpopulation of chondrocytes (cluster 3). This clinically relevant cluster was predicted to be the main chondrocyte cluster responsible for maintaining cellular homeostasis and anti-senescence. Specifically, we uncovered a set of the key leading-edge proteins of cluster 3 by validating the robustness of the above results using another human chondrocyte single-cell RNA-sequencing data set, consisting of 24,675 chondrocytes. Furthermore, cartilage samples from clinical patients and experimental mouse models of OA were used to evaluate the expression patterns of these leading-edge proteins, and the results indicated that NDRG2, TSPYL2, JMJD6 and HMGB2 are closely associated with OA pathogenesis and might play critical roles in modulating cellular homeostasis and anti-senescence in chondrocytes.ConclusionOur study revealed a novel subpopulation of chondrocytes that are critical for anti-progression of OA and the corresponding master regulator proteins, which might serve as therapeutic targets in OA.

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“…The serum-free medium was substituted with the complete medium and further incubated for 48 hours. Next, the cellular RNA was separated to verify the transfection validity [ 25 ]. Vectors, CAB39, Si-NC, and Si-CAB39 were devised and integrated by GenePharma (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Calcium-binding protein 39 overexpression promotes macrophages from ‘M1’ into ‘M2’ phenotype and improves chondrocyte damage in osteoarthritis by activating the AMP-activated protein kinase/sirtuin 1 axis

et al. 2022

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Osteoarthritis (OA) is a degenerative joint disease that affects cartilage and its peripheral tissues. Up-regulation of Calcium-binding protein 39 (CAB39) has a significant protective effect on osteoblasts, but the role and related molecular mechanisms of CAB39 in OA have not yet been reported. CAB39 overexpression and knockdown models were set up in chondrocytes (ATDC5) and macrophages (RAW264.7). The OA cell model was induced in ATDC5 cells with IL-1β (10 ng/mL). Cell viability was tested by the cell counting kit-8 assay, apoptosis was checked by flow cytometry. Western blot was applied for checking the expression of MMP3, MMP13, Aggrecan, the AMPK/Sirt-1 pathway, apoptosis-related proteins (Bax, Bcl-2, and Caspase-3), and macrophage phenotypic markers (CD86, iNOS, CD206, and Arg1). An OA model was constructed in mice, and CAB39 overexpression plasmids were administered to the knee cavity of the OA model mice. As a result, CAB39 was down-regulated in IL-1β-treated chondrocytes and OA mice. Overexpressing CAB39 enhanced ATDC5 cell viability and choked IL-1β-mediated apoptosis. Overexpression of CAB39 boosted the polarization of macrophages from M1-phenotype into M2 phenotype. In addition, overexpressing CAB39 facilitated the AMPK/Sirt-1 pathway activation, and AMPK inhibitors reversed the protective effect of CAB39 overexpression on chondrocytes. Moreover, CAB39 exhibited anti-inflammatory effects in OA mice by activating the AMPK/Sirt-1 pathway. Collectively, overexpressing CAB39 heightened macrophages’ M2 polarization and declined chondrocyte injury in OA by activating the AMPK/Sirt-1 pathway. Abbreviations AMPK: AMP-activated protein kinaseArg1: arginase 1Bax: Bcl-2-associated X proteinBcl-2: B-cell lymphoma-2CAB39: Calcium-binding protein 39CM: Conditioned mediumDMM: destabilization of the medial meniscusECM: extracellular matrixELISA: enzyme-linked immunosorbent assayFCM: Flow cytometryIL-1β: interleukin-1βIL-4: interleukin-4IL-6: interleukin-6IL-10: interleukin-10IFN – γ: Interferon-gammaIHC: ImmunohistochemistryiNOS: Inducible nitric oxide synthaseLKB1: liver kinase B1MMP3: Matrix metalloproteinase3MMP13:Matrix metalloproteinase13NF-κB: NF-kappaBOA: OsteoarthritisqRT-PCR: Quantitative reverse transcription-polymerase chain reactionRT: room temperatureSirt-1: sirtuin 1STRAD: STE20-related adaptor alphaWB: Western blot

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Transcription factor Krüppel-like factor 5-regulated N-myc downstream-regulated gene 2 reduces IL-1β-induced chondrocyte inflammatory injury and extracellular matrix degradation

Abstract: Zhu (2021) Transcription factor Krüppel-like factor 5-regulated N-myc downstream-regulated gene 2 reduces IL-1β-induced chondrocyte inflammatory injury and extracellular matrix degradation, Bioengineered, 12:1, 7020-7032,

Cited by 7 publications

References 35 publications

KLF transcription factors in bone diseases

KLF transcription factors in bone diseases

Single-cell protein activity analysis reveals a novel subpopulation of chondrocytes and the corresponding key master regulator proteins associated with anti-senescence and OA progression

Calcium-binding protein 39 overexpression promotes macrophages from ‘M1’ into ‘M2’ phenotype and improves chondrocyte damage in osteoarthritis by activating the AMP-activated protein kinase/sirtuin 1 axis

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