Integration of transcriptomic and epigenomic analyses uncovered Lrrc15 as a potential contributing factor to cartilage damage in osteoarthritis
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ABSTRACT:
PROVIDER: PRJNA732467 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14638120.fastq.gz | Fastqsanger.gz | |||
| SRR14638121.fastq.gz | Fastqsanger.gz | |||
| SRR14638122.fastq.gz | Fastqsanger.gz | |||
| SRR14638123.fastq.gz | Fastqsanger.gz | |||
| SRR14638124.fastq.gz | Fastqsanger.gz |
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Project description:Objective: We used the destabilization of the medial meniscus (DMM) model to identify temporal changes in DNA methylation patterns associated with structural and transcriptomic changes in cartilage during osteoarthritis (OA) progression. Methods: RNA sequencing (RNAseq) and Reduced Representation Oxidative Bisulfite Sequencing (RRoxBS) analyses were done in total RNA and DNA obtained from micro-dissected cartilage at 4 and 12 weeks after DMM surgery. Murine and human primary chondrocytes were used to evaluate the cytokine- and methylation-dependent changes in the expression of Lrrc15, and its contribution to IL-1beta-induced changes in chondrocytes. Results: We identified time-dependent alterations in epigenomic patterns in cartilage after DMM, with significant changes in 5mC and 5hmC methylation comparing samples retrieved at 4 and 12 weeks after surgery. Integration of RNAseq and RRoxBS datasets identified Lrrc15 as a hypomethylated gene with increased expression at 4 weeks after surgery. We confirmed LRRC15 immunostaining in OA cartilage, and experiments in human and murine primary chondrocytes showed that the expression of Lrrc15 is DNA methylation-dependent and induced by IL1beta and TNFalfa in vitro. Knockdown experiments showed that Lrrc15 contributes to the IL1beta-driven expression of catabolic genes relevant to OA, including Mmp13. Significance: Our integrative analyses showed that the structural progression of OA is accompanied by transcriptomic and dynamic epigenomic changes in articular cartilage. We found that Lrrc15 is differentially methylated and expressed in OA cartilage, and that it may contribute to the cytokine-driven responses of OA chondrocytes. A better understanding of the role of Lrrc15 in cartilage homeostasis and osteoarthritis may help us uncover targets with therapeutic potential.
2021-09-01 | GSE175486 | GEO
Project description:Successfully replacing damaged cartilage with tissue-engineered constructs requires integration with the host tissue and could benefit from leveraging the native tissue's intrinsic healing capacity; however, efforts are limited by a poor understanding of how cartilage repairs minor defects. Here, we investigated the conditions that foster natural cartilage tissue repair to identify strategies that might be exploited to enhance the integration of engineered/ grafted cartilage with host tissue. We damaged porcine articular cartilage explants and using a combination of pulsed SILAC-based proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies reveal that integration of damaged cartilage surfaces is not driven by neo-matrix synthesis, but rather local depletion of proteoglycans. ADAMTS4 expression and activity are upregulated in injured cartilage explants, but integration could be reduced by inhibiting metalloproteinase activity with TIMP3. These observations suggest that catabolic enzyme-mediated proteoglycan depletion likely allows existing collagen fibrils to undergo cross-linking, fibrillogenesis, or entanglement, driving integration. Catabolic enzymes are often considered pathophysiological markers of osteoarthritis. Our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions and in osteoarthritis, but could also be harnessed in tissue engineering strategies to mediate repair. Statement of significance: Cartilage tissue engineering strategies require graft integration with the surrounding tissue; however, how the native tissue repairs minor injuries is poorly understood. We applied pulsed SILACbased proteomics, ultrastructural imaging, and catabolic enzyme blocking strategies to a porcine cartilage explant model and found that integration of damaged cartilage surfaces is driven by catabolic enzyme-mediated local depletion of proteoglycans. Although catabolic enzymes have been implicated in cartilage destruction in osteoarthritis, our findings suggest that damage-induced upregulation of metalloproteinase activity may be a part of a healing response that tips towards tissue destruction under pathological conditions. They also suggest that this natural cartilage tissue repair process could be harnessed in tissue engineering strategies to enhance the integration of engineered cartilage with host tissue.
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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
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Project description:Cartilage mineralization is a tightly controlled process, imperative for skeletal growth and fracture repair. However, in osteoarthritis (OA), cartilage mineralization may impact the joint range of motion, inflict pain and may increase chances for joint effusion. Here we attempt to understand the link between inflammation and cartilage mineralization by targeting SIRT1 and LEF1, both reported to have contrasting effects on cartilage.
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Project description:Osteoarthritis is characterized by cartilage destruction, chronic inflammation, and subchondral sclerosis. Evidence showed that nuclear receptor family is closely associated with cartilage damage in an unclear molecular mechanism. Here, we investigated the role and molecular mechanism of the retinoic acid receptor-related orphan receptor-α (RORα), an important member of nuclear receptor, in regulating cartilage degradation and osteoarthritis pathogenesis. Investigation to osteoarthritis clinical specimen showed that the degree of RORα elevation is positively correlated with the severity of osteoarthritis and cartilage damage. In an in vivo osteoarthritis models induced by anterior crucial ligament transaction, intraarticularly injection of siRora adenovirus reversed the cartilage damage. RORα knock-down increased the protein expression level of anabolic factor such as type II collagen, Aggrecan, and decreased the expression of catabolic factor. RNA-seq data suggested IL-6/STAT3 pathway is significantly down-regulated. Mechanistically, RORα knock-down decreased the expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, which includes interaction with STAT3 and IL6 promoter. Taken together, our findings indicated the pivotal role of RORα/IL-6/STAT3 axis in osteoarthritis progression and confirmed RORα knock-down exerted therapeutic effect in human chondrocyte thus providing a potential drug target in osteoarthritis therapy.
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