Transcriptome analysis after GPX4 knockdown in primary mouse chondrocyte（mcc）
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE190184 | GEO | 2022/02/18
REPOSITORIES: GEO
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Project description:To investigate the gene expression profiling in bone diseases including osteoathritis (OA) and bone cancer (chondrosarcoma), different chondrocytes were isolated and assessed. For OA, the paired normal and OA chondrocytes were isolated from patient with total knee replacement surgery. Identification and delineation of dys-regulated genes between normal and OA chondrocytes and the regulatory mechanisms may provide the opportunity to treat OA. Also, the comparison with normal chondrocyte and chondrosarcoma cell lline (JJ012) gene expression profiling to identify the novel targets for chondrosarcoma therapies.
2024-09-25 | GSE276764 | GEO
Project description:Transcriptome analysis after GPX4 knockdown in primary mouse chondrocyte（mcc）
| PRJNA786223 | ENA
Project description:Chondrocyte senescence underlies osteoarthritis (OA). However, the pathogenesis of chondrocyte senescence remains largely unclear. Here we report that TRIM15 is a critical regulator in chondrocyte senescence. TIRM15 is highly expressed in chondrocytes of senescent cartilage from human OA patients and aged mice. Using gain- and loss-of-function studies, we further identify that TRIM15 facilitates chondrocyte senescence. Notably, conditional deletion of TRIM15 in chondrocytes severely impairs skeletal growth, partially due to the fact that embryonic chondrocyte senescence is disturbed. Compared with Col2a1-CreERT2/TRIM15flox/flox mice, TRIM15flox/flox mice exhibits accelerated OA phenotype, increased senescence markers and senescence-associated secretory phenotype (SASP) during aging. Mechanistically, TRIM15 binds with YAP and directly mediates K48-linked YAP ubiquitination at K254, which interrupts the interaction between YAP and AMOT, leading to enhanced YAP nuclear translocation. Intra-articular injection of AAV5-Trim15 shRNA decelerates OA progression in mice. Collectively, these findings indicate that targeting TRIM15 reshapes aging cartilage microenvironment and protects against OA.
2025-02-24 | GSE281609 | GEO
Project description:Invariant natural killer T (iNKT) cells are a group of innate like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared to CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of Glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFNg producing NKT1 subset. RNAseq analysis revealed IFNg signaling, cell cycle regulation, as well as mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial ROS in Gpx4 KO iNKT cells. Ferroptosis inhibitor, iron chelator, vitamin E and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Lastly, vitamin E rescued iNKT cell population in Gpx4 KO mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
2024-08-20 | GSE270485 | GEO
Project description:Avascular soft tissues of the skeletal system, including articular cartilage, have an extremely limited healing capacity, in part due to their low metabolic activity. No drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Therefore, mesenchymal stromal cell (MSC)-based regenerative therapies are increasingly common in the treatment of OA, but questions regarding their clinical efficacy and mechanisms of action remain unanswered. Our group recently reported that mitochondrial dysfunction is one of the earliest responses of cartilage to injury, resulting in chondrocyte death, extracellular matrix degeneration, and ultimately OA. MSCs have been found to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. To investigate how gene expression changes in stressed chondrocytes, and therefore how they might elicit mitochondrial donation from MSCs, we developed a custom quantitative PCR panel of relevant genes involved in chondrocyte metabolism and OA. We cultured chondrocytes under conditions known induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and non-physiologic culture conditions (hyperoxia and hyperglycemia). We found that expression of gap junction alpha 1 (GJA1), the gene that encodes the Cx43 protein, was increased in hyperoxia. The senescence associated markers, cyclin-dependent kinase inhibitor 2A (CDKN2A) and tissue inhibitor of metalloproteinases 1 (TIMP1), were also increased in hyperoxia. In addition, hyperoxia caused chondrocytes to increase the expression of the antioxidant enzyme, SOD2. This work provides insights into the chemical and environmental conditions that can alter gene expression in chondrocytes. Further, this provides supporting evidence to our hypothesis that stressed chondrocytes may trigger mitochondrial donation from MSCs may via direct or indirect signaling involving the inflammation- and senescence-related genes identified in the present study.
2022-08-10 | GSE202788 | GEO
Project description:Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, Ahlbäck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT. Keywords: time course, cell type comparison, tissue engineered cartilage; osteoarthritis; Hyaff-11 scaffold; human chondrocytes; gene expression profiling; regenerative medicine; differentiation potential
2009-09-02 | GSE16464 | GEO
Project description:Comparative analysis of gene expression in cultured primary keratinocytes isolated from newborn control (K14-cre; GPx4fl/+) and knockout (K14-cre; GPx4fl/fl) mice. Selenoproteins are essential for skin function, as targeted abolition of selenoproteins in epidermal tissue results in newborn mice manifesting gross abnormalities of skin and hair, accompanied by retarded growth and premature death. To investigate whether lack of a single selenoprotein could induce similar phenotypic effect in mice, we generated keratinocyte-specific knockout mice lacking glutathione peroxidase 4 (GPx4), an essential selenoprotein in skin, to examine phenotypic changes resulting from the lack of GPx4 in skin. Ablation of GPx4 results in focal alopecia and disturbed hair follicle morphogenesis, with GPx4 being essential during early stages of hair follicle morphogenesis as well as for keratinocyte adhesion and proliferation in culture. We have generated mice with selective removal of the GPx4 gene in keratinocytes under the control of Keratin-14-cre (K14-cre) promoter. Comparative microarray analysis was performed on RNA samples taken from pooled primary keratinocytes from knockout and control mice from the same litter. Array replicates were performed using RNA samples from three different litters.
2012-12-06 | E-GEOD-34215 | biostudies-arrayexpress
Project description: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.
2025-01-15 | GSE285234 | GEO
Project description:Examination of the genome-wide distribution of 5hmC in osteoarthritic chondrocytes compared to normal chondrocytes in order to elucidate the effect on OA-specific gene expression. 5hmC-sequencing was performed and data was compared with microarray gene expression data to identify genes with differential expression between normal and OA chondrocytes that are potentially under epigenetic regulation. High-throughput sequencing of 5hmC in 4 normal and 4 OA chondrocyte samples.
2015-06-30 | E-GEOD-64393 | biostudies-arrayexpress
Project description:Osteoarthritis (OA) is a widespread age-related joint disease caused by the gradual loss of chondrocyte function along with age. Here, we found that UFMylation modification was lower-leveled in senescent cartilage, mediated chondrocyte senescence and OA phenotypes through targeting CAVIN1, which acted as a stimulator in chondrocyte senescence, mainly through promoting CPT1 expression and activating fatty acid β-oxidation (FAO). Physiologically, FAO was at a very low level in chondrocytes, while the anomalous activation of FAO accelerated chondrocyte senescence. UFMylation of CAVIN1 promoted its binding with TRIP12, leading to ubiquitination degradation. Therefore, UFMylation played a pivotal role in post-translationally modification of CAVIN1. Polymeric micellar nanoparticles (NPs) conjugated with UFM1 improved the stability of UFM1 recombinant protein (UFM1-rp), and extended the retention time of UFM1-rp in the mouse joint cavity. The administration of UFM1 into mouse joints using an advanced NP delivery system is effective in attenuating age-related pathogenesis. Therefore, we uncovered a previously unknown mechanism, UFM1-CAVIN1-CPT1 axis, in the protection of OA progression and constructed a new drug for OA treatment, and have provided important preliminary evidence toward the translation of our findings into clinical usage.
2024-04-22 | GSE264185 | GEO