Cartilage microRNA dysregulation during the onset and progression of mouse osteoarthritis is independent of aggrecanolysis and overlaps with candidates from end-stage human disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE101574 | GEO | 2017/11/30
SECONDARY ACCESSION(S): PRJNA394853
REPOSITORIES: GEO
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Project description:The purpose of this study is to characterize the expression profile of microRNAs and their target mRNAs in cartilage and subchondral bone (SCB) in a mouse model of post-traumatic osteoarthritis (OA).
2017-11-30 | GSE101573 | GEO
Project description:The purpose of this study is to characterize the expression profile of microRNAs and their target mRNAs in cartilage and subchondral bone (SCB) in a mouse model of post-traumatic osteoarthritis (OA).
2017-11-30 | GSE93008 | GEO
Project description:Cartilage microRNA dysregulation during the onset and progression of mouse osteoarthritis is independent of aggrecanolysis and overlaps with candidates from end-stage human disease
| PRJNA394853 | ENA
Project description:Oxidative stress is proposed as an important factor in osteoarthritis (OA).To investigate the expression of the three superoxide dismutase (SOD) antioxidant enzymes in OA.SOD expression was determined by real-time PCR and immunohistochemistry using human femoral head cartilage. SOD2 expression in Dunkin-Hartley guinea pig knee articular cartilage was determined by immunohistochemistry. The DNA methylation status of the SOD2 promoter was determined using bisulphite sequencing. RNA interference was used to determine the consequence of SOD2 depletion on the levels of reactive oxygen species (ROS) using MitoSOX and collagenases, matrix metalloproteinase 1 (MMP-1) and MMP-13, gene expression.All three SOD were abundantly expressed in human cartilage but were markedly downregulated in end-stage OA cartilage, especially SOD2. In the Dunkin-Hartley guinea pig spontaneous OA model, SOD2 expression was decreased in the medial tibial condyle cartilage before, and after, the development of OA-like lesions. The SOD2 promoter had significant DNA methylation alterations in OA cartilage. Depletion of SOD2 in chondrocytes increased ROS but decreased collagenase expression.This is the first comprehensive expression profile of all SOD genes in cartilage and, importantly, using an animal model, it has been shown that a reduction in SOD2 is associated with the earliest stages of OA. A decrease in SOD2 was found to be associated with an increase in ROS but a reduction of collagenase gene expression, demonstrating the complexities of ROS function.
| S-EPMC3789136 | biostudies-literature
Project description:BackgroundOsteoarthritis has been associated with a plethora of pathological factors and one which has recently emerged is chondrocyte endoplasmic reticulum (ER) stress. ER stress is sensed by key ER-resident stress sensors, one of which is activating transcription factor 6 (ATF6). The purpose of this study is to determine whether increased ER stress plays a role in OA.MethodsOA was induced in male wild-type (+/+), ColIITgcog (c/c) and Atf6α-/- mice by destabilisation of the medial meniscus (DMM). c/c mice have increased ER stress in chondrocytes via the collagen II promoter-driven expression of ER stress-inducing Tgcog. Knee joints were scored histologically for OA severity. RNA-seq was performed on laser-micro-dissected RNA from cartilage of +/+ and c/c DMM-operated mice.ResultsIn situ hybridisation demonstrated a correlation between the upregulation of ER stress marker, BiP, and early signs of proteoglycan loss and cartilage damage in DMM-operated +/+ mice. Histological analysis revealed a significant reduction in OA severity in c/c mice compared with +/+ at 2 weeks post-DMM. This chondroprotective effect in c/c mice was associated with a higher ambient level of BiP protein prior to DMM and a delay in chondrocyte apoptosis. RNA-seq analysis suggested Xbp1-regulated networks to be significantly enriched in c/c mice at 2 weeks post-DMM. Compromising the ER through genetically ablating Atf6α, a key ER stress sensor, had no effect on DMM-induced OA severity.ConclusionOur studies indicate that an increased capacity to effectively manage increases in ER stress in articular cartilage due either to pre-conditioning as a result of prior exposure to ER stress or to genetic pre-disposition may be beneficial in delaying the onset of OA, but once established, ER stress plays no significant role in disease progression.
| S-EPMC6737683 | biostudies-literature
Project description:Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.
| S-EPMC7508826 | biostudies-literature
Project description:An impact injury model of early stage osteoarthritis (OA) progression was developed using a mechanical insult to an articular cartilage surface to evaluate differential gene expression changes over time and treatment. Porcine patellae with intact cartilage surfaces were randomized to one of three treatments: nonimpacted control, axial impaction (2000?N), or a shear impaction (500?N axial, with tangential displacement to induce shear forces). After impact, the patellae were returned to culture for 0, 3, 7, or 14 days. At the appropriate time point, RNA was extracted from full-thickness cartilage slices at the impact site. Quantitative real-time PCR was used to evaluate differential gene expression for 18 OA related genes from four categories: cartilage matrix, degradative enzymes and inhibitors, inflammatory response and signaling, and cell apoptosis. The shear impacted specimens were compared to the axial impacted specimens and showed that shear specimens more highly expressed type I collagen (Col1a1) at the early time points. In addition, there was generally elevated expression of degradative enzymes, inflammatory response genes, and apoptosis markers at the early time points. These changes suggest that the more physiologically relevant shear loading may initially be more damaging to the cartilage and induces more repair efforts after loading.
| S-EPMC4248372 | biostudies-literature
Project description:PurposeTo investigate compositional changes of knee cartilage at the site of newly appearing cartilage lesions and the surrounding cartilage 1-4 years prior to lesion onset using quantitative T2-measurements.MethodsFifty-seven cartilage plates with newly appearing cartilage lesions from 45 knees (cases) and 52 plates from 26 control knees from the Osteoarthritis Initiative (OAI) cohort (controls) were evaluated. Using MRI T2-mapping, composition of local (the site of future lesions) and surrounding cartilage (remainder of the cartilage plate) was assessed 1-4 years prior to lesion onset. Analogous cartilage ROIs in control plates without cartilage lesions were assessed over 1-4 years. Mixed models were used to compare T2-means and change rates between local and surrounding cartilage within cases and controls, and to compare change rates in local and surrounding cartilage between cases and controls, adjusting for covariates.ResultsFour years prior to lesion onset, we found that local cartilage ROIs had higher T2-values compared to the surrounding cartilage. No such differences were found in control plates. In cases mean local T2-values were persistantly elevated compared to the surrounding cartilage prior to lesion onset reaching significance 1 year prior (+2.94 ms, p = 0.012). T2-values of the surrounding cartilage were also persistantly higher in cases compared to controls, reaching significance 2 years prior to lesion onset (+3.61 ms, p = 0.003).ConclusionThe findings of our study support the concept of compositional cartilage changes as a mechanism for cartilage degradation and that both diffuse and focal changes of cartilage composition within a cartilage plate precede the development of cartilage lesions.
| S-EPMC6482329 | biostudies-literature
Project description:Recent studies have shown that superoxide dismutase 1 (SOD1), SOD2, and SOD3 are significantly decreased in human osteoarthritic cartilage. SOD activity is a marker that can be used to comprehensively evaluate the enzymatic capacities of SOD1, SOD2, and SOD3; however, the trend of SOD activity in end-stage osteoarthritic tissues remains unknown. In the present study, we found that SOD activity in end-stage osteoarthritic synovium of the knee was significantly lower than that in control synovium without the influence of age. The SOD activity was significantly lower in the end-stage knee osteoarthritic cartilage than in the control, but a weak negative correlation was observed between aging and SOD activity. However, SOD activity in end-stage hip osteoarthritic cartilage was significantly lower than that in control cartilage without the influence of aging. The relationship between osteoarthritis and SOD activity was stronger than the relationship between aging and SOD activity. These results indicate that direct regulation of SOD activity in joint tissues may lead to suppression of osteoarthritis progression.
| S-EPMC6141073 | biostudies-literature
Project description:ObjectiveThis study constructs a risk score for patients' progression to end-stage knee osteoarthritis (OA) within 4 years.DesignThe Osteoarthritis Initiative (OAI) was a longitudinal study of the onset and progression of knee OA. Using a recent definition of end-stage knee OA, we implement interval-censored survival forests to select predictors of this endpoint. We fit an interval-censored Cox model for time to end-stage knee OA, using the selected predictors. The risk score is the Cox model's fitted linear combination of the nine selected baseline structural and symptomatic knee OA variables.ResultsWe fit our models on a training set of 2,701 patients, and we evaluate on an independent test set of 1,436 patients. On the test sample, we observe a concordance index of 0.86 between risk score and time to end-stage, AUC of 0.87 for predicting end-stage within 24, 36, and 48 months, and positive predictive values that increase with the risk score. This risk stratification algorithm could enrich clinical trial patient enrollment. By enrolling test sample patients with scores above a threshold, a trial could have included 91% of test set patients who reach end-stage within 4 years while only enrolling 45% of the test sample.ConclusionUsing statistical methods, we construct and validate an interpretable risk score for time to end-stage knee OA. This score can help disease-modifying OA treatment developers to select candidates with the highest risk of fast-progressing knee OA.
| S-EPMC7575033 | biostudies-literature