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Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183956 | GEO | 2022/09/11

REPOSITORIES: GEO

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Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [ChIP-seq]

Project description:ChIP-seq with anti-HA tag antibody in TC28a2 cells transfected with HA-KLF4.We performed genome-wide analysis for KLF4-DNA association in TC28a2 human chondrocyte cells, to elucidate regulatory mechanisms of chondrogenic genes by KLF4.

2022-09-11 | GSE183955 | GEO

Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [DRUG-seq]

Project description:We performed global gene expression analysis in Ad-KLF4-, Ad-EGFP- and non-transduced TC28a2 human chondrocyte cells, to study genes regulated by KLF4 comprehensively.

2022-09-11 | GSE183954 | GEO

Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis

Project description:Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis

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Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [ChIP-seq]

Project description:Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [ChIP-seq]

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Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [DRUG-seq]

Project description:Krüppel-like factors-4 and -2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis [DRUG-seq]

| PRJNA762488 | ENA

Mocetinostat activates Kruppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.

Project description:Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.

| S-EPMC10544226 | biostudies-literature

Mocetinostat activates Kruppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis

Project description:Kruppel-like factor-4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissue cells. To explore novel therapeutic candidates for osteoarthritis (OA), high-throughput screening (HTS) with 11,948 compounds was per-formed using a reporter cell line detecting endogenous KLF4 activation. Eighteen com-pounds were identified through the HTS and confirmed in a secondary screen. Among them, mocetinostat, a class I histone deacetylase inhibitor, had the best biological activi-ties. Mocetinostat upregulated chondrogenic genes in human chondrocytes, meniscal cells, and mesenchymal stem cells, while it down-regulated hypertrophic, inflammatory and cat-abolic genes in those cells and synoviocytes. Intraperitoneal administration of mocetino-stat into mice reduced severity of OA-associated changes in cartilage, meniscus and syno-vium and improved pain behaviors. Global gene expression and proteomics analyses re-vealed that regenerative and protective effects of mocetinostat depended on peroxisome proliferator-activated receptor gamma coactivator 1-alpha. These findings qualify mocetino-stat as a potential candidate for disease modifying OA drugs.

2023-01-11 | MSV000091049 | MassIVE

MicroRNAs: Important Epigenetic Regulators in Osteoarthritis.

Project description:Multiple mechanisms are implicated in the development of primary osteoarthritis (OA), in which genetic and epigenetic factors appear to interact with environmental factors and age to initiate the disease and stimulate its progression. Changes in expression of microRNAs (miRs) contribute to development of osteoarthritis. Numerous miRs are involved in cartilage development, homeostasis and degradation through targeting genes expressed in this tissue. An important regulator of gene expression in human cartilage is miR-140, which directly targets a gene coding aggrecanase ADAMTS-5, that cleaves aggrecan in cartilage. This miR is considered a biological marker for cartilage and its level significantly decreases in OA cartilage. On the other hand, increased expression of miR-146a in early OA inhibits two other cartilage-degrading enzymes: MMP13 and ADAMTS4, and may provide a useful tool in developing treatments for OA. The COL2A1 gene, encoding collagen type II, which is the most abundant structural protein of the cartilage, is silenced by miR-34a and activated by miR-675. Every year, new targets of cartilage miRs are validated experimentally and this opens new possibilities for new therapies that control joint destruction and stimulate cartilage repair. At the same time development of next-generation sequencing technologies allows to identify new miRs involved in cartilage biology.

| S-EPMC4293743 | biostudies-literature

The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression.

Project description:Osteoarthritis (OA) is a common, painful disease. Currently OA is incurable, and its etiology largely unknown, partly due to limited understanding of OA as a whole-joint disease. Here we report that two homologous microRNAs, miR-204 and miR-211, maintain joint homeostasis to suppress OA pathogenesis. Specific knockout of miR-204/-211 in mesenchymal progenitor cells (MPCs) results in Runx2 accumulation in multi-type joint cells, causing whole-joint degeneration. Specifically, miR-204/-211 loss-of-function induces matrix-degrading proteases in articular chondrocytes and synoviocytes, stimulating articular cartilage destruction. Moreover, miR-204/-211 ablation enhances NGF expression in a Runx2-dependent manner, and thus hyper-activates Akt signaling and MPC proliferation, underlying multiplex non-cartilaginous OA conditions including synovial hyperplasia, osteophyte outgrowth and subchondral sclerosis. Importantly, miR-204/-211-deficiency-induced OA is largely rescued by Runx2 insufficiency, confirming the miR-204/-211-Runx2 axis. Further, intraarticular administration of miR-204-expressing adeno-associated virus significantly decelerates OA progression. Collectively, miR-204/-211 are essential in maintaining healthy homeostasis of mesenchymal joint cells to counteract OA pathogenesis.

| S-EPMC6599052 | biostudies-literature

Tryptase regulation of joint lubrication and inflammation in osteoarthritis

Project description:Proteoglycan 4 (PRG4) is an extracellular matrix protein that maintains homeostasis through its boundary lubricating and anti-inflammatory properties. Altered expression and function of PRG4 have been associated with joint inflammatory diseases, including osteoarthritis (OA). We found that mast cell tryptase cleaves PRG4 in a dose- and time-dependent manner, which was confirmed by silver stain gel electrophoresis and mass spectrometry. Tryptase-treated PRG4 resulted in a reduction of lubrication. Compared to full-length, processed PRG4 was shown to further activate NF-B expression in cells overexpressing TLR2, -4, and -5. In the destabilization of the medial meniscus (DMM) model of OA in rat, tryptase and PRG4 colocalized at the site of injury in knee cartilage and were associated with disease severity. Primary synovial fibroblasts from OA patients or healthy subjects treated with tryptase and/or PRG4, and synovial cells from OA patients, were subjected to a quantitative shotgun proteomics and proteome changes were characterized, further supporting the role of NF-B activation. We identified tryptase as a modulator of joint lubrication via the processing of PRG4 in OA.

2023-03-04 | PXD037040 | Pride

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