Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk.

ABSTRACT: During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

SUBMITTER: Richard D

PROVIDER: S-EPMC7179902 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Regulatory constraint and selection during human knee evolution drive modern osteoarthritis risk

Project description:The evolution of human bipedalism exposed the knee to unique biomechanical challenges, requiring changes in knee anatomy giving rise to the modern-day configuration. In order to better understand the relationship between derived knee morphology and the genetic factors associated with osteoarthritis risk, we performed epigenetic profiling of murine forelimb/hindlimb growth plates to identify regulatory elements shaping formation of specific knee structures, identifying signals of ancient positive selection upon which more recent genetic drift overlaps risk-associated loci. Our functional analyses of an osteoarthritis-risk variant within a reproducibly-associated locus establishes a novel model for studying this degenerative disease.

2020-04-16 | GSE122877 | GEO

Regulatory constraint and selection during human knee evolution drive modern osteoarthritis risk

Project description:Regulatory constraint and selection during human knee evolution drive modern osteoarthritis risk

| PRJNA506781 | ENA

Impaired chondrocyte U3 snoRNA expression in osteoarthritis impacts the chondrocyte protein translation apparatus.

Project description:Although pathways controlling ribosome activity have been described to regulate chondrocyte homeostasis in osteoarthritis, ribosome biogenesis in osteoarthritis is unexplored. We hypothesized that U3 snoRNA, a non-coding RNA involved in ribosomal RNA maturation, is critical for chondrocyte protein translation capacity in osteoarthritis. U3 snoRNA was one of a number of snoRNAs with decreased expression in osteoarthritic cartilage and osteoarthritic chondrocytes. OA synovial fluid impacted U3 snoRNA expression by affecting U3 snoRNA gene promoter activity, while BMP7 was able to increase its expression. Altering U3 snoRNA expression resulted in changes in chondrocyte phenotype. Interference with U3 snoRNA expression led to reduction of rRNA levels and translational capacity, whilst induced expression of U3 snoRNA was accompanied by increased 18S and 28S rRNA levels and elevated protein translation. Whole proteome analysis revealed a global impact of reduced U3 snoRNA expression on protein translational processes and inflammatory pathways. For the first time we demonstrate implications of a snoRNA in osteoarthritis chondrocyte biology and investigated its role in the chondrocyte differentiation status, rRNA levels and protein translational capacity.

| S-EPMC7417995 | biostudies-literature

Epigenetic Regulation in Knee Osteoarthritis.

Project description:Osteoarthritis (OA) is a complicated disease with both hereditary and environmental causes. Despite an increase in reports of possible OA risk loci, it has become clear that genetics is not the sole cause of osteoarthritis. Epigenetics, which can be triggered by environmental influences and result in transcriptional alterations, may have a role in OA pathogenesis. The majority of recent research on the epigenetics of OA has been focused on DNA methylation, histone modification, and non-coding RNAs. However, this study will explore epigenetic regulation in OA at the present stage. How genetics, environmental variables, and epigenetics interact will be researched, shedding light for future studies. Their possible interaction and control processes open up new avenues for the development of innovative osteoarthritis treatment and diagnostic techniques.

| S-EPMC9304589 | biostudies-literature

MicroRNA-128a represses chondrocyte autophagy and exacerbates knee osteoarthritis by disrupting Atg12.

Project description:Chondrocyte loss is a prominent feature of osteoarthritis (OA). Autophagy is indispensable in maintaining the metabolic activities of cells exposed to deleterious stress. The contribution of microRNA signaling to chondrocyte autophagy in OA development remains elusive. We uncovered an association between poor autophagy and increased miR-128a expressions in articular chondrocytes of patients with end-stage knee OA and in a rat anterior cruciate ligament transection (ACLT) model for OA development. Cartilage matrix degradation and severe OA histopathology was evident upon forced miR-128a expression within the articular compartment. Intra-articular injections with miR-128a antisense oligonucleotide stabilized chondrocyte autophagy and slowed ACLT-mediated articular tissue destruction, including cartilage erosion, synovitis, osteophyte formation, and subchondral plate damage. In vitro, miR-128 signaling hindered Atg12 expression, LC3-II conversion, and autophagic puncta formation through targeting the 3'-untranslated region of Atg12. It increased apoptotic programs, diminishing cartilage formation capacity of articular chondrocytes. Inactivating histone methyltransferase EZH2 reduced methyl histone H3K27 enrichment in the miR-128a promoter and upregulated miR-128a transcription in inflamed chondrocytes. Taken together, miR-128a-induced Atg12 loss repressed chondrocyte autophagy to aggravate OA progression. EZH2 inactivation caused H3K27 hypomethylation to accelerate miR-128a actions. Interruption of miR-128a signaling attenuated chondrocyte dysfunction and delayed OA development. Our data provide new insights into how miR-128a signaling affects chondrocyte survival and articular cartilage anabolism and highlight the potential of miR-128a targeting therapy to alleviate knee OA.

| S-EPMC6134128 | biostudies-literature

MicroRNA-375 exacerbates knee osteoarthritis through repressing chondrocyte autophagy by targeting ATG2B.

Project description:ObjectiveThis study aimed to explore the underlying mechanism of miR-375 in exacerbating osteoarthritis (OA).ResultsMiR-375 expression were upregulated in OA cartilage tissues, whereas ATG2B expression was decreased. MiR-375 targeted ATG2B 3' UTR and inhibited its expression in the chondrocytes, and then suppressed autophagy and promoted endoplasmic reticulum stress (ERs). The apoptosis rate of chondrocytes was increased after being transfected with miR-375 mimics. In vivo results further verified that inhibition of miR-375 could relieve OA-related symptoms.ConclusionmiR-375 can inhibit the expression of ATG2B in chondrocytes, suppress autophagy and promote the ERs. It suggests that miR-375 could be considered to be a key therapy target for OA.MethodsDifferential expression analyses for mRNA and miRNA microarray datasets from ArrayExpress were performed. MiR-375 and ATG2B expressions in cartilage tissues were detected by qRT-PCR. Dual luciferase assay was applied to verify the targeting relationship between ATG2B and miR-375. In vitro, the role of miR-375 on chondrocyte autophagy and ERs was investigated by western blot and immunofluorescence. The apoptotic rate was quantified by flow cytometry. In vivo, OA mice model was established, HE and Safranin O and Fast Green staining, as well as the OARSI and modified Mankin scores, were applied to measure the OA cartilage damage severity.

| S-EPMC7202526 | biostudies-literature

Epigenetic Regulation of Chondrocyte Catabolism and Anabolism in Osteoarthritis.

Project description:Osteoarthritis (OA) is one of the most prevalent forms of joint disorder, associated with a tremendous socioeconomic burden worldwide. Various non-genetic and lifestyle-related factors such as aging and obesity have been recognized as major risk factors for OA, underscoring the potential role for epigenetic regulation in the pathogenesis of the disease. OA-associated epigenetic aberrations have been noted at the level of DNA methylation and histone modification in chondrocytes. These epigenetic regulations are implicated in driving an imbalance between the expression of catabolic and anabolic factors, leading eventually to osteoarthritic cartilage destruction. Cellular senescence and metabolic abnormalities driven by OA-associated risk factors appear to accompany epigenetic drifts in chondrocytes. Notably, molecular events associated with metabolic disorders influence epigenetic regulation in chondrocytes, supporting the notion that OA is a metabolic disease. Here, we review accumulating evidence supporting a role for epigenetics in the regulation of cartilage homeostasis and OA pathogenesis.

| S-EPMC4546939 | biostudies-literature

Predicting knee osteoarthritis risk in injured populations.

Project description:Individuals who suffered a lower limb injury have an increased risk of developing knee osteoarthritis. Early diagnosis of osteoarthritis and the ability to track its progression is challenging. This study aimed to explore links between self-reported knee osteoarthritis outcome scores and biomechanical gait parameters, whether self-reported outcome scores could predict gait abnormalities characteristic of knee osteoarthritis in injured populations and, whether scores and biomechanical outcomes were related to osteoarthritis severity via Spearman's correlation coefficient.A cross-sectional study was conducted with asymptomatic participants, participants with lower-limb injury and those with medial knee osteoarthritis. Spearman rank determined relationships between knee injury and outcome scores and hip and knee kinetic/kinematic gait parameters. K-Nearest Neighbour algorithm was used to determine which of the evaluated parameters created the strongest classifier model.Differences in outcome scores were evident between groups, with knee quality of life correlated to first and second peak external knee adduction moment (0.47, 0.55). Combining hip and knee kinetics with quality of life outcome produced the strongest classifier (1.00) with the least prediction error (0.02), enabling classification of injured subjects gait as characteristic of either asymptomatic or knee osteoarthritis subjects. When correlating outcome scores and biomechanical outcomes with osteoarthritis severity only maximum external hip and knee abduction moment (0.62, 0.62) in addition to first peak hip adduction moment (0.47) displayed significant correlations.The use of predictive models could enable clinicians to identify individuals at risk of knee osteoarthritis and be a cost-effective method for osteoarthritis screening.

| S-EPMC5544598 | biostudies-other

DUSP4 alleviates LPS-induced chondrocyte injury in knee osteoarthritis via the MAPK signaling pathway.

Project description:Knee osteoarthritis (KOA) is characterized by cartilage damage, and the associated pathogenesis is complex. The expression of dual specificity protein phosphatase 4 (DUSP4) is significantly decreased in osteoarthritis (OA); however, the specific role and mechanism underlying DUSP4 in OA are yet to be elucidated. ATDC5 cells were treated with lipopolysaccharide (LPS) to establish the cell injury model. The expression levels of DUSP4 were decreased in OA chondrocytes, demonstrated by reverse transcription-quantitative PCR and western blot analysis. Following overexpression of DUSP4 by cell transfection, Cell Counting Kit-8, ELISA, TUNEL and western blotting assays were used to detect the cell viability, oxidative stress, inflammation and apoptosis levels of LPS-induced ATDC5 cells. Overexpression of DUSP4 inhibited the activation of the MAPK signaling pathway, thereby reducing oxidative stress levels, inflammatory response and apoptosis in the OA cell model. The mechanisms underlying DUSP4 in OA were further explored following the addition of MAPK signaling pathway agonist, phorbol 12-myristate 13-acetate (PMA). The addition of PMA reversed the inhibitory effects of DUSP4 overexpression on oxidative stress, inflammatory response and apoptosis in cells. In summary, DUSP4 alleviated LPS-induced chondrocyte injury in KOA via the MAPK signaling pathway.

| S-EPMC8506912 | biostudies-literature

miR-129-3p alleviates chondrocyte apoptosis in knee joint fracture-induced osteoarthritis through CPEB1.

Project description:BackgroundOsteoarthritis (OA), a refractory disease, is one of the leading contributors for disability worldwide. Since chondrocyte is the only resident cell in cartilage, this study aims to explore the roles of miR-129-3p and CPEB1 in chondrocyte apoptosis in knee joint fracture-induced OA.MethodsCartilage was collected from 20 OA patients who underwent total knee replacement (OA group) and 20 patients with knee contusion (normal group). Then, miR-129-3p and CPEB1 levels in the cartilage were quantified by qRT-PCR. Primary rat chondrocytes in the knee were isolated and identified by toluidine blue staining and immunofluorescent staining of type II collagen. OA cellular models were induced by TNF-α treatment, in which miR-129-3p and CPEB1 expressions were assessed. Subsequently, cell viability, apoptosis, and the expression levels of apoptotic protein and caspase-3 were measured. Dual luciferase reporter assay identified the interaction between miR-129-3p and CPEB1.ResultsPatients in the OA group had decreased miR-129-3p expression and increased CPEB1 expression than those in the normal group. TNF-α treatment successfully induced the OA cellular model. Downregulated miR-129-3p and upregulated CPEB1 expressions were found in OA-treated chondrocytes. miR-129-3p overexpression or CPEB1 knockdown improved chondrocyte viability and attenuated apoptosis, and vice versa. miR-129-3p negatively regulated CPEB1, thus ameliorating apoptosis and enhancing cell viability.ConclusionmiR-129-3p negatively targeted CPEB1 to facilitate chondrocyte viability and hamper apoptosis.

| S-EPMC7684967 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data