RNA-sequencing of mechanical stress induced osteoarthritis-like damage in aged human cartilage explants treated with the anti-deiodinase iopanoic acid
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ABSTRACT:
PROVIDER: EGAS00001006242 | EGA |
REPOSITORIES: EGA
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Project description:Osteoarthritis (OA) is a polygenic disease of older people resulting in the breakdown of cartilage within articular joints. Although a leading cause of disability, there are no disease-modifying therapies. Evidence is emerging to support the origins of OA in skeletogenesis. Whilst methylation QTLs (mQTLs) co-localizing with OA GWAS signals have been identified in aged human cartilage and used to identify effector genes and variants, such analyses have never been conducted during human development. Here, for the first time, we have investigated the developmental origins of OA genetic risk at seven well-characterized OA risk loci, comprising 39 OA-mQTL CpGs, in human fetal limb (FL) and cartilage (FC) tissues using a range of molecular genetic techniques. We compared our results to aged cartilage samples (AC) and identified significant OA-mQTLs at 14 CpGs and 29 CpGs in FL and FC tissues, respectively. Differential methylation was observed at 26 sites between fetal and aged cartilage, with the majority becoming actively hypermethylated in old age. Notably, 6/9 OA effector genes showed allelic expression imbalances during fetal development. Finally, we conducted ATAC-sequencing in cartilage from the developing and aged hip and knee to identify accessible chromatin regions, and found enrichment for transcription factor-binding motifs including SOX9 and FOS/JUN. For the first time, we have demonstrated the activity of OA-mQTLs and expression imbalance of OA effector genes during skeletogenesis. We show striking differences in the spatiotemporal function of these loci, contributing to our understanding of OA aetiology, with implications for the timing and strategy of pharmacological interventions.
2022-10-26 | GSE214394 | GEO
Project description:Osteoarthritis (OA) affects nearly 10% of the population of the United States and other industrialized countries and, at present, short of surgical joint replacement, there is no therapy available that can reverse the progression of the disease OA. Adenosine, acting at its A2A receptor (A2AR), is a critical autocrine factor for maintenance of cartilage homeostasis. Here we report that injection of liposomal suspensions of a selective A2AR agonist, CGS21680, significantly reduced OA cartilage damage in a rat model of established post-traumatic OA (PTOA). Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with PTOA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone.
2020-09-01 | GSE146813 | GEO
Project description:Changes in the mechanical homeostasis of the temporomandibular joint (TMJ) can lead to the initiation and progression of degenerative arthropathies such as osteoarthritis (OA). Cells sense and engage with their mechanical microenvironment through interactions with the extracellular matrix. In the mandibular condylar cartilage, the pericellular microenvironment is composed of type VI collagen. NG2/CSPG4 is a transmembrane proteoglycan that binds with type VI collagen, and has been implicated in the cell stress response through mechanical loading-sensitive signaling networks including ERK 1/2. The objective of this study is to define the role of NG2/CSPG4 in the initiation and progression of TMJ OA and to determine if NG2/CSPG4 engages ERK 1/2 in a mechanical loading dependent manner. In vivo, we induced TMJ OA in control and NG2/CSPG4 knockout mice using a surgical destabilization approach. In control mice, NG2/CSPG4 is depleted during the early stages of TMJ OA and NG2/CSPG4 knockout mice have more severe cartilage degeneration, elevated expression of key OA proteases, and suppression of OA matrix synthesis genes. In vitro, we characterized the transcriptome and protein from control and NG2/CSPG4 knockout cells and found significant dysregulation of the ERK 1/2 signaling axis. To characterize the mechanobiological response of NG2/CSPG4, we applied mechanical loads on cell-agarose-collagen scaffolds using a compression bioreactor and illustrate that NG2/CSPG4 knockout cells fail to mechanically activate ERK 1/2 and are associated with changes in the expression of the same key OA biomarkers measured in vivo. Together, these findings implicate NG2/CSPG4 in the mechanical homeostasis of TMJ cartilage and in the progression of degenerative arthropathies including OA.
2022-09-24 | GSE214077 | GEO
Project description:Temporomandibular joint osteoarthritis (TMJ-OA), a subtype of temporomandibular joint dysfunction (TMD), is characterized by progressive cartilage degradation, subchondral bone erosion, and chronic pain. Although there has been extensive research on TMJ-OA, its etiology remains unknown. Age, hormonal factors, and excessive mechanical stress on the TMJ are proposed risk factors for TMJ-OA. Using microarrays, we discovered two disease susceptibility genes that have been suggested to be involved in the pathogenic mechanism of TMJ-OA.
2020-09-18 | GSE158106 | GEO
Project description:Evidences indicate that mechanical loading plays an important role in osteoarthritis (OA) progression, while the specific pathological changes of the synovium under excessive mechanical loading are unclear. Results showed excessive mechanical loading caused pro-inflammatory of synovial macrophages, which has been confirmed to exists in OA. High Rapgef3 expression level was found in RNA sequencing of RAW246.7 subjected to 0.5Hz-20%-cyclic tensile strain. We verified this in the synovium of OA patients and DMM-OA mice. Interestingly, the Rapgef3 content of chondrocytes was very low. Primary chondrocytes treated with Rapgef3 alone did not show metabolic phenotype, but an OA phenotype appeared when treated with Rapgef3-stimulated macrophage culture supernatant. Mechanically, excessive mechanical loading activated p65-NF-κB pathway through Rapgef3, which promoted the inflammatory of macrophage, resulting in severe articular cartilage injury. Intra-articular Rapgef3 knockout reversed synovitis and cartilage degeneration, which might provide a therapeutic target for osteoarthritis.
2024-11-04 | GSE280230 | GEO
Project description:Osteoarthritis (OA) is the most prevalent joint disease with the typifying feature being the progressive degradation of articular cartilage during disease progression. In this study we used whole transcriptome RNA-seq as a tool to compare gene expression changes between age-matched osteoarthritic human hip OA cartilage (n=10) compared to control (neck of femur fracture) cartilage (n=6) [GSE107308]. All cartilage was from patients undergoing acetabulofemoral joint replacement. Cartilage RNA was isolated from cartilage within 2 hr of joint replacement surgery, mRNA was polyA purified and transcript expression was analysed using 78-base paired-end sequencing generating on average 28 million reads/sample sequencing. The data shows excellent correlation with our previous microarray data but identifies significantly more differentially expressed transcripts plus novel transcript variants, several of which have been validated by real-time qPCR. Our work sheds further light on chondrocyte transcriptome expression and highlights gene expression changes and novel transcripts potentially important in osteoarthritis progression
2019-03-01 | GSE111357 | GEO
Project description:Articular cartilage degeneration, which may lead to osteoarthritis (OA), is a normal component of the aging process, but its underlying mechanism remains unknown. We found that chondrocytes exhibited an energy metabolism shift from glycolysis to oxidative phosphorylation (OXPHOS) during aging. Reprogrammed cartilage metabolism by parkin ablation decreased OXPHOS and increased glycolysis, with ameliorated aging-related OA. Metabolomics analysis indicated that lauroyl-L-carnitine (LLC) was decreased in aged cartilage, but increased in parkin-deficient cartilage. In vitro, LLC improved the cartilage matrix synthesis of OA chondrocytes. In vivo, intraarticular injection of LLC in mice with anterior cruciate ligament transaction (ACLT) ameliorated OA. These results suggest that metabolic changes are regulated by parkin-impaired cartilage during aging, and targeting the metabolomic changes by supplementation with LLC is a promising treatment strategy for ameliorating OA.
2024-06-18 | GSE249510 | GEO
Project description:Articular cartilage degeneration, which may lead to osteoarthritis (OA), is a normal component of the aging process, but its underlying mechanism remains unknown. We found that chondrocytes exhibited an energy metabolism shift from glycolysis to oxidative phosphorylation (OXPHOS) during aging. Reprogrammed cartilage metabolism by parkin ablation decreased OXPHOS and increased glycolysis, with ameliorated aging-related OA. Metabolomics analysis indicated that lauroyl-L-carnitine (LLC) was decreased in aged cartilage, but increased in parkin-deficient cartilage. In vitro, LLC improved the cartilage matrix synthesis of OA chondrocytes. In vivo, intraarticular injection of LLC in mice with anterior cruciate ligament transaction (ACLT) ameliorated OA. These results suggest that metabolic changes are regulated by parkin-impaired cartilage during aging, and targeting the metabolomic changes by supplementation with LLC is a promising treatment strategy for ameliorating OA.
2024-06-18 | GSE249509 | GEO
Project description:Osteoarthritis (OA) is a degenerative joint disease with a substantial health economic burden. There is no current treatment; instead, disease management targets the main symptoms (pain and stiffness) and culminates in joint replacement surgery. OA is a disease of cartilage degeneration, but the molecular changes leading to the development of OA are still poorly understood. In this study we compare methylation, gene transcription and protein abundance at the genome-wide level in individually-matched samples of chondrocytes extracted from affected and relatively healthy articular cartilage across 12 OA patients undergoing total knee replacement. Integration analysis highlights genes that are consistently affected at multiple levels, including AQP1, CLEC3B and COL1A1, and also relevant biological pathways such as extracellular matrix organization, collagen catabolism and proteolysis. Collectively these results provide a first view of the comprehensive molecular landscape underpinning OA development and point to potential therapeutic avenues.
2018-10-24 | PXD002014 | Pride
Project description:Osteoarthritis (OA) is characterised by an irreversible degeneration of articular cartilage. Here we show that the BMP-antagonist Gremlin 1 (Grem1) marks a bipotent chondrogenic and osteogenic progenitor cell population within the articular surface. Notably, these progenitors are depleted by injury-induced OA and increasing age. OA is also caused by ablation of Grem1 cells in mice. Transcriptomic and functional analysis in mice found that articular surface Grem1-lineage cells are dependent on Foxo1 and ablation of Foxo1 in Grem1-lineage cells caused OA. FGFR3 signalling was confirmed as a promising therapeutic pathway by administration of pathway activator, FGF18, resulting in Grem1-lineage chondrocyte progenitor cell proliferation, increased cartilage thickness and reduced OA. These findings suggest that OA, in part, is caused by mechanical, developmental or age-related attrition of Grem1 expressing articular cartilage progenitor cells. These cells, and the FGFR3 signalling pathway that sustains them, may be effective future targets for biological management of OA.
2023-09-19 | GSE242732 | GEO