Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233714 | GEO | 2023/05/30
REPOSITORIES: GEO
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Project description:Targeting MMP13 directly by RNA interference (RNAi) silenced MMP13 in a murine post-traumatic osteoarthritis (PTOA) and was found to have broad effects on overall joint health, including both the articular cartilage and surrounding hard and soft tissues. To further characterize the global impacts of targeted MMP13 inhibition, the mechanical loading mouse model was applied with samples were harvested at 4 weeks to capture an intermediate stage of disease. The nanoString nCounter Inflammation panel was used to broadly quantify gene expression of the knee joint samples (articular cartilage, meniscal, and synovial tissue). Abstract: Osteoarthritis (OA) is a debilitating and prevalent chronic disease, but there are no approved disease modifying OA drugs (DMOADs), only pharmaceuticals for pain management. OA progression, particularly for post-traumatic osteoarthritis (PTOA), is associated with inflammation and enzymatic degradation of the extracellular matrix. In particular, matrix metalloproteinase 13 (MMP13) breaks down collagen type 2 (CII), a key structural component of cartilage extracellular matrix, and consequently, matrix degradation fragments perpetuate inflammation and a degenerative cycle that leads to progressive joint pathology. Here, we tested extracellular matrix-binding MMP13 RNA interference (RNAi) nanoparticles (NPs) as a DMOAD. The retention approach pursued here deviates from the convention of targeting specific cell types (e.g., through cell surface receptors) and instead leverages a monoclonal antibody (mAbCII) that targets extracellular CII that becomes uniquely accessible in OA-damaged cartilage. CII monoclonal antibody-functionalized nanoparticles carrying small interfering ribonucleic acid (siRNA) (mAbCII-siNPs) create an in situ NP depot for retention and potent activity within OA joints. The mAbCII-siNPs loaded with MMP13 siRNA (mAbCII-siNP/siMMP13) potently suppressed MMP13 expression (95% silencing) in TNFα-stimulated chondrocytes in vitro and had higher binding to trypsin-damaged porcine cartilage than control NPs. In an acute mechanical injury mouse model of PTOA, mAbCII-siNP/siMMP13 achieved 80% reduction in MMP13 expression (p = 0.00231), whereas control siNP/siMMP13 achieved only 55% silencing. In a more severe, longer-term PTOA model, weekly mAbCII-siNP/siMMP13 treatment provided significant protection of cartilage integrity (0.45+/-.3 vs 1.6+/-.5 on the OARSI scale; p=0.0013) and overall joint structure (1.3+/-.6 vs 2.8+/-.2 on the Degenerative Joint Disease scale; p=0.0418), including reduction of osteophyte formation (siMMP13 vs siNEG: 0.088+/-0.074 vs 0.47+/-0.107 mm femoral osteophyte outgrowth; p<0.0001). Multiplexed gene expression analysis of 254 inflammation-related genes showed that MMP13 inhibition suppressed clusters of genes associated with tissue restructuring, angiogenesis, innate immune response, and proteolysis. Finally, in benchmarking studies, intra-articular mAbCII-siNPs better reduced OA disease progression relative to either one time or weekly treatment with the clinical gold standard steroid methylprednisolone. Here, we introduce the concept of anchoring to unique local extracellular matrix signatures to sustain retention and increase delivery efficacy of biologics with intracellular activity and also validates the promise of MMP13 RNAi as a DMOAD in a clinically-relevant therapeutic context.
2021-04-17 | GSE171031 | GEO
Project description:Discrimination of rheumatoid arthritis (RA) patients from patients with other inflammatory/degenerative joint diseases or healthy individuals purely on the basis of genes differentially expressed in high-throughput data has proven very difficult. Thus, the present study sought to achieve such discrimination by employing a novel unbiased approach using rule-based classifiers. Three multi-center genome-wide transcriptomic data sets (Affymetrix HG- U133 A/B) from a total of 79 individuals, including 20 healthy controls (control group - CG), as well as 26 osteoarthritis (OA) and 33 RA patients, were used to infer rule- based classifiers to discriminate the disease groups. The rules were ranked with respect to Kiendl’s statistical relevance index, and the resulting rule set was optimized by pruning. The rule sets were inferred separately from data of one of three centers and applied to the two remaining centers for validation. All rules from the optimized rule sets of all centers were used to analyze their biological relevance applying the software Pathway Studio. The optimized rule sets for the three centers contained a total of 29, 20, and 8 rules (including 10, 8, and 4 rules for ‘RA’), respectively. The mean sensitivity for the prediction of RA based on six center-to-center tests was 96% (range 90% to 100%), that for OA 86% (range 40% to 100%). The mean specificity for RA prediction was 94% (range 80% to 100%), that for OA 96% (range 83.3% to 100%). The average overall accuracy of the three different rule-based classifiers was 91% (range 80% to 100%). Unbiased analyses by Pathway Studio of the gene sets obtained by discrimination of RA from OA and CG with rule-based classifiers resulted in the identification of the pathogenetically and/or therapeutically relevant interferon-gamma and GM-CSF pathways. First-time application of rule-based classifiers for the discrimination of RA resulted in high performance, with means for all assessment parameters close to or higher than 90%. In addition, this unbiased, new approach resulted in the identification not only of pathways known to be critical to RA, but also of novel molecules such as serine/threonine kinase 10. Synovial tisssue from healthy joints, OA joints, and RA joints.
2014-02-21 | E-GEOD-55235 | biostudies-arrayexpress
Project description:Preserved and affected cartilage from 17 knees and 14 hip joints were sampled from patients undergoing joint replacement surgery, due to primary OA. 17 knees and 14 hip joints
2015-11-06 | E-GEOD-63106 | biostudies-arrayexpress
Project description:Genome wide gene expression was determined in paired samples of OA affected and preserved cartilage of the same joint using microarray analysis for 33 patients of the RAAK-study. Among the 1717 genes that were significantly different expressed between OA affected and preserved cartilage we found significant enrichment for genes involved in skeletal development (e.g. TNFRSF11B and FRZB). Also several inflammatory genes such as CD55, PTGES and TNFAIP6, previously identified in within-joint analyses as well as in analyses comparing preserved cartilage from OA affected joints versus healthy cartilage were among the top genes. A notable new gene was NGF, highly up-regulated in OA cartilage. To identify gene expression profiles associated with OA processes in articular cartilage and determine pathways responsive to the disease process gene expression profiles of paired preserved and OA affected cartilage samples of the same joint were determined.
2014-07-28 | E-GEOD-57218 | biostudies-arrayexpress
Project description:Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. In this study we investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. CD14+ cells from BM and blood of RA and osteoarthritis (OA) patients were profiled with Affymetrix HG U133 Plus 2.0 Arrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilization. Cytometric profiling determined monocyte subsets of CD14++CD16-, CD14++CD16+ and CD14+CD16+ cells in BM, blood and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. Investigation of genes differentially expressed between RA and OA monocytes by co-expression analysis with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+ monocytes in RA blood. Patterns associated with TNF/LPS stimulation were weak and more pronounced in RA blood than BM. Cytometric phenotyping of cells in BM and blood disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+ monocytes in RA blood, as suggested by transcriptome data. Monocyte activation in SF was characterized by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. Accelerated monocytopoiesis, BM egress and migration into inflamed joints characterise increased monocyte turnover in RA. Predominant activation in the joint suggests local and primary stimulants, which may promote also adaptive immune triggering through monocytes, thus indicating their importance for diagnostic and therapeutic strategies.
2017-07-05 | GSE100786 | GEO
Project description:Various forms of chronic arthritis like osteoarthritis (OA) or rheumatoid arthritis (RA) are major causes of disability and represent a global burden on health care systems. Inter- and intraindividual differences in the phenotype of arthritis often prevent early diagnosis and effective treatment. Previously, we suggested that site-specific differences in the joint stroma influence the development and the outcome of arthritis and showed that the long non-coding RNA HOTAIR is expressed exclusively in synovial fibroblasts (SF) of lower joints. Here, we further analysed the function of HOTAIR in SF and in arthritis development. We show that joint-specific HOTAIR expression in SF is stronlgy imprinted in the chromatin landscape of SF by epigenetic mechanisms. Nevertheless, HOTAIR expression in knee SF was downregulated by inflammatory cytokines. Accordingly, HOTAIR was more expressed in OA tissues than in RA tissues. Downregulation of HOTAIR regulated relevant arthritis pathways by epigenetic and transcriptional mechanisms and modified the migratory function of SF, decreased SF mediated osteoclastogenesis, and increased the attraction of B cells by SF. We propose that HOTAIR downregulation in inflammation epigenetically regulates important pathways and functions in SF, and thus modulates the phenotype of arthritis in lower extremity joints.
2023-01-01 | GSE185440 | GEO
Project description:Preserved and affected cartilage from 17 knees and 14 hip joints were sampled from patients undergoing joint replacement surgery, due to primary OA.
2015-11-06 | GSE63106 | GEO
Project description:Mechanical Stimuli are arguably the most important aetiolgical factors in osteoarthritis (OA) development. Not only do we see disease arising from joints where the cartilage has sustained direct (e.g. intraarticular fracture) or indirect (e.g. meniscal injury) trauma, but mechanical factors are considered, at least partly, to explain the disease associations with aging and obesity. It is now well established that OA is not simply due to repeated wear and tear, leading to attrition of the articular surfaces, but that it requires activation of a number of inflammatory genes, which drive catabolic protease activity in the joint. These enzymes lead to breakdown of the major extracellular matrix components of cartilage, namely type II collagen, and the proteoglycan, aggrecan. Although it is unclear precisely which enzymes are responsible for matrix breakdown in human OA, Glasson et al showed that deletion of the aggrecan degrading enzyme, ADAMTS5 substantially protected the joint from surgically induced murine OA suggesting that it is a major aggrecanase in the mouse. This study was part of a wider study using the surgical model of murine OA, induced by destabilising the medial meniscus (DMM), to confirm the dependence of joint loading on disease progression and to reveal mechanosensitive genes within the joint which may be involved in the development of OA. Using this model we, and others, have shown that there is a robust degradation of articular cartilage over 4-12wks in male C57B/6 mice. We identified the gene response in joints early following induction of OA, prior to cartilage degradation, by extracting RNA from whole joints (after skin and muscle had been removed) 6hrs, 3 days and 7 days following sham and DMM surgery. An Affymetrix ST1 gene array was performed. Significantly regulated genes (>1.4 fold above naive and sham samples at any timepoint), or those considered to have a putative role in OA pathogenesis were selected for quantitative validation using Taqman low density microfluidic card arrays (TLDA). Gene expression in whole knee joints at 3 early time points post DMM surgery (before cartilage loss), 6hrs, 3days and 7days was examined. Two controls were identified, the first control consisted of age matched naïve mice that had undergone 15 minutes of anaesthesia but were not operated on (0hrs post surgery). The second control included mice which had undergone sham surgery (capsulotomy alone). For this RNA was taken at the same time points post surgery as DMM samples (6hrs, 3days and 7days). There were three biological replicates per condition (total of 21 samples). The right (ipsilateral) knee joint was taken and RNA extracted and processed for microarray analysis using the Affymetrix Mouse Gene 1.0 st v1 platform.
2011-01-13 | E-GEOD-26475 | biostudies-arrayexpress
Project description:All the synovial tissue specimens for TMT relative quantitative proteomics and further experiments were obtained from the patients with RA or OA undergoing surgical joint replacement at the clinical of joint surgery (Xi'an Hong Hui Hospital, Xi'an Jiaotong University, China). The diagnosis of the patients were accorded to the criteria of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) in 2010.a quantitative proteomic profiling of synovial tissue obtained from RA and OA patients was carried out by using TMT labeling followed by high resolution mass spectrometry analysis. We have identified 4822 proteins out of which 510 proteins were found to be differentially expressed by ≥1.2 fold change in the synovial tissue from RA verses OA patients.
2021-12-30 | PXD027703 | Pride
Project description:Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage loss, bone remodeling, synovial inflammation, and significant joint pain, often resulting in disability. Injury to the synovial joint such as the anterior cruciate ligament (ACL) tear is the major cause of OA in young adults. Currently, there are no approved therapies available to prevent joint degeneration or rebuild articular cartilage destroyed by OA, primarily because our understanding of the cellular and molecular changes that contribute to joint damage is very limited. The synovial joint is a complex structure composed of several tissues including articular cartilage, subchondral bone, synovium, synovial fluid, and tensile tissues including tendons and ligaments. In the present study, using single-cell RNA sequencing (scRNA-seq), we examined the cellular heterogeneity in articular cartilage from mouse knee joints and determined the knee joint injury-induced early molecular changes in the chondrocytes that could contribute to OA.
2021-06-19 | GSE172500 | GEO