Dataset Information

TRIM15 drives chondrocyte senescence and osteoarthritis progression

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281609 | GEO | 2025/02/24

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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, AhlbÃ¤ck 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. Experiment Overall Design: Gene expression profiles of monolayer cultures (ML; passage 2) and Hyaff-11 scaffold cultures (3D; 14 days in vitro) of chondrocytes from 3 normal donors (ND; underwent ACT treatment) and 3 donors suffering from Osteoarthritis (OA; underwent knee replacement surgery) were determined. Comparative analyses between 3D and ML cultures (3D vs. ML) were performed to assess differentiation capacity of ND and OA chondrocytes. Furthermore, OA-related differences were determined comparing OA and ND monolayers as well as scaffold cultures (each OA vs. ND).

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.

Project description:Osteoarthritis (OA) of the hand is a common disease resulting in pain and impaired function. The pathogenesis of hand OA (HOA) is elusive and models to study it have not been described so far. Culture of chondrocytes is a model to study the development of cartilage degeneration, which is a hallmark of OA and well established in OA of the knee and hip. In the current study we investigated the feasibility human chondrocyte culture derived from proximal interphalangeal (PIP) finger joints of dissecting room cadavers. Index and middle fingers without signs of osteoarthritis were obtained from 30 cadavers using two different protocols. Hyaline cartilage from both articulating surfaces of the proximal interphalangeal (PIP) joint was harvested and digested in collagenase. Cultured chondrocytes were monitored for contamination, viability, and expression of chondrocyte specific genes. Chondrocytes derived from knee joints of the cadavers were cultured under identical conditions. Gene expression comparing chondrocytes from PIP and knee joints was carried out using Affymetrix GeneChip Human 2.0 ST arrays. The resulting differentially expressed genes were validated by real-time PCR and immunohistochemistry.Chondrocytes harvested up to 101 hours after death of the donors were viable. mRNA expression of collagen 2A1, aggrecan and Sox9 was significantly higher in chondrocytes as compared to cultured fibroblasts. Comparison of gene expression by chondrocytes from PIP and knee joints yielded 528 differentially expressed genes. Chondrocytes from the same joint region had a higher grade of similarity than chondrocytes of the same individual. These results were validated using real-time PCR and immunohistochemistry.We demonstrate for the first time a reliable method for culture of chondrocytes derived from PIP joints. PIP chondrocytes show a specific gene expression pattern and could be used as tool to study cartilage degeneration in HOA. Three samples of cultured chondrocytes from knee and proximal interphalangeal finger joints were compared. Gene expression of the four most differentially regulated genes was confirmed by real-time PCR in 10 independent samples.

Dataset Information

TRIM15 drives chondrocyte senescence and osteoarthritis progression

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets