Single-cell genomic profile of articular chondrocytes from CIA rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE230500 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting synovial joints and leading to cartilage damage and bone loss. This destruction is promoted by activated fibroblast-like synoviocytes (FLS) that show an invasive and migratory phenotype. The mechanisms of FLS activation are unknown, but evidence suggests that pre-damaged extracellular matrix (ECM) of the cartilage can trigger FLS activation. Integrin α11β1 might be involved in the activation, as it is highly increased in the synovium of RA patients and hTNFtg mice, an RA mouse model. Since TNFα is the major cytokine induced in RA, we treated murine chondrocytes with TNFα to produce a damaged, RA-like matrix. Comparison to healthy chondrocyte matrix revealed decreased ECM proteins, including several collagens and proteoglycans, increased matrix-degrading proteins and elevated levels of inflammatory cytokines. FLS responded to those differences in the damaged chondrocyte matrix with a matrix-remodeling and pro-inflammatory phenotype characterized by expressing genes involved in matrix degradation and increased production of CLL11 and CCL19. Damaged chondrocyte matrix induced increased Itga11 expression in FLS, which correlates with the increased α11β1 amounts in RA patients. FLS deficient in integrin α11β1 released lower amounts of inflammation-associated cytokines but did not reveal significant differences from the response of wild type FLS to a damaged, RA-like matrix. Our results demonstrate differences in healthy and RA-like chondrocyte ECM and distinctly different responses of wt FLS to damaged versus healthy ECM.
2025-01-14 | PXD049800 | Pride
Project description:Rheumatoid arthritis (RA) leads to progressive destruction of articular structures. Despite recent progress in controlling inflammation and pain, little cartilage repair has yet been observed. This in vitro study aims to determine the role of chondrocytes in RA-related cartilage destruction and antirheumatic drug-related regenerative processes. Human chondrocytes were three-dimensionally cultured in alginate beads. To determine the RA-induced gene expression pattern, human chondrocytes were stimulated with supernatant of RA synovial fibroblasts (RASF) and normal donor synovial fibroblasts (NDSF), respectively. To examine antirheumatic drug response signatures, human chondrocytes were stimulated with supernatant of RASF that have been treated with disease-modifying antirheumatic drugs (DMARD; azathioprine, sodium aurothiomalate, chloroquine phosphate, methotrexate), non-steroidal anti-inflammatory drugs (NSAID; piroxicam, diclofenac) or steroidal anti-inflammatory drugs (SAID; methylprednisolone, prednisolone). Genome-wide expression profiling with oligonucleotide microarrays was used to determine differentially expressed genes. Real-time RT-PCR and ELISA were performed for validation of microarray data. Following antirheumatic treatment, microarray analysis disclosed a reverted expression of 94 RA-induced chondrocyte genes involved in inflammation/NF-κB signalling, cytokine/chemokine activity, immune response, proliferation/differentiation and matrix remodelling. Hierarchical clustering analysis showed that treatment of RASF with the DMARD azathioprine, gold sodium thiomalate and methotrexate resulted in chondrocyte gene expression signatures that were closely related to the âhealthyâ pattern. Treatment with the SAID methylprednisolone and prednisolone strongly reverted the RA-related chondrocyte gene expression, in particular the expression of genes involved in inflammation/NF-κB and cytokine/chemokine activity. The NSAID piroxicam and diclofenac and the DMARD chloroquine phosphate had only moderate to marginal effects. Pathway analysis determined major mechanisms of drug action, for example pathways of cytokine-cytokine receptor interaction, TGF-β/TLR/Jak-STAT signalling and ECM-receptor interaction were targeted. This in vitro study provides a comprehensive molecular insight into the antirheumatic drug response signatures in human chondrocytes, thereby revealing potential molecular targets, pathways and mechanisms of drug action involved in chondrocyte regeneration. Thus, the present study may contribute to the development of novel therapeutic chondro-protective compounds and strategies. Experiment Overall Design: Drug-related suppression of gene expression in activated chondrocytes was determined by genome-wide microarray analysis. Chondrocytes were stimulated with supernatant of RASF and NDSF. Effect of treatment with DMARDs, NSAIDs and glucocorticoids was tested by treating RASF prior to collection of supernatant. Two RNA pools were analyzed for each group (RASF-stimulated NDSF stimulated and RASF-treated), each pool consisting of equal amounts of RNA from three different donors.
2008-10-25 | E-GEOD-12860 | biostudies-arrayexpress
Project description:The destruction of bone and cartilage results in a loss of joint functionality, critically impairing the quality of life in arthritis patients. Synovial fibroblasts (SFs) critically contribute to the pathogenesis of rheumatoid arthritis (RA) by acquiring either a pro-inflammatory or tissue-destructive phenotype. To explore the molecular mechanisms underlying the pathogenic fibroblast phenotype in arthritis, we performed single-cell RNA sequencing (scRNA-seq) on the synovial cells which were isolated from collagen-induced arthritis (CIA) mice.
2022-07-06 | GSE192504 | GEO
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis - Age Dependant
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000549.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000549 | BioModels
Project description:Baker2013 - Cytokine Mediated Inflammation in
Rheumatoid Arthritis
This model by Baker M. 2013, describes
the interaction between pro and anti-inflammatory cytokine
signalling in rheumatoid arthritis.
Using two ordinary differential equations, the first model
[BIOMD0000000550]
analyses bifurcation and describes different pathological states by
altering inflammatory regulation parameters.
The second model
[BIOMD0000000549]
includes the effect that ageing has on pro-inflammatory signalling,
allowing for time-dependant properties and disease progression to
be observed. The author also describes potential dosing for
reversal of the disease state.
This model is described in the article:
Mathematical modelling of
cytokine-mediated inflammation in rheumatoid arthritis.
Baker M, Denman-Johnson S, Brook BS,
Gaywood I, Owen MR.
Math Med Biol 2013 Dec; 30(4):
311-337
Abstract:
Rheumatoid arthritis (RA) is a chronic inflammatory disease
preferentially affecting the joints and leading, if untreated,
to progressive joint damage and disability. Cytokines, a group
of small inducible proteins, which act as intercellular
messengers, are key regulators of the inflammation that
characterizes RA. They can be classified into pro-inflammatory
and anti-inflammatory groups. Numerous cytokines have been
implicated in the regulation of RA with complex up and down
regulatory interactions. This paper considers a two-variable
model for the interactions between pro-inflammatory and
anti-inflammatory cytokines, and demonstrates that mathematical
modelling may be used to investigate the involvement of
cytokines in the disease process. The model displays a range of
possible behaviours, such as bistability and oscillations,
which are strongly reminiscent of the behaviour of RA e.g.
genetic susceptibility and remitting-relapsing disease. We also
show that the dose regimen as well as the dose level are
important factors in RA treatments.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000550.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000550 | BioModels
Project description:Lung disease is the most overrepresented cause of death in rheumatoid arthritis (RA). Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA), a model that recapitulates features of RA-associated interstitial lung disease (RA-ILD). As patients with RA-ILD demonstrate unique circulating monocyte subpopulations, this study aims to characterize lung infiltrating monocytes/macrophages in a mouse model of RA-ILD and determine whether reducing these cells mitigates the development of lung disease. Autoimmune-prone DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for up to 5 weeks and CIA induction. Experimental groups included Sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS), and CIA+LPS (CIA/LPS). Lung disease was assessed by longitudinal imaging, lung function measurements, bronchoalveolar lavage fluid, lung tissues, and lung histopathology. Cell subpopulations were analyzed by single cell RNA-sequencing. Unsupervised clustering revealed 16 discrete clusters among the experimental groups with 2 robust clusters characterized as infiltrating inflammatory monocytes/macrophages for both CIA+LPS and CIA. The interaction of inhalation-induced airway inflammation and autoimmune arthritis results in lung disease associated with uniquely activated infiltrating inflammatory monocytes-macrophages that mediate adverse lung consequences. Whereas the induced monocyte/Mɸ immunophenotype is more aligned to CIA than endotoxin exposure, co-exposure modeling renders unique features that potentially inform the pathogenesis and treatment of RA-ILD.
2025-04-30 | GSE284234 | GEO
Project description:Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. This study investigates the therapeutic potential of secretome derived from adipose tissue mesenchymal stem cells (ASCs) in mitigating inflammation and promoting cartilage repair in an in vitro model of OA. Our in vitro model comprised chondrocytes inflamed with TNF. To assess the therapeutic potential of secretome, inflamed chondrocytes were treated with it and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and extracellular matrix markers were measured. In addition, secretome-treated chondrocytes were subject to a microarray analysis to determine which genes were upregulated and which were downregulated. Treating TNF-inflamed chondrocytes with secretome in vitro inhibits the NF-κB pathway, thereby mediating anti-inflammatory and anti-catabolic effects. Additional protective effects of secretome on cartilage are revealed in the inhibition of hypertrophy markers such as RUNX2 and COL10A1, increased production of COL2A1 and ACAN and upregulation of SOX9. These findings suggest that ASC-derived secretome can effectively reduce inflammation, promote cartilage repair, and maintain chondrocyte phenotype. This study highlights the potential of ASC-derived secretome as a novel, non-cell-based therapeutic approach for OA, offering a promising alternative to current treatments by targeting inflammation and cartilage repair mechanisms.
2024-10-22 | GSE239343 | GEO
Project description:We have studied the expression profile of 3D cultured human chondrocytes that were stimulated with supernatant of synovial fibroblasts derived from a RA patient (RASF=HSE cell line) and from a normal donor (NDSF=K4IM cell line), respectively. For this purpose, passage 2 human chondrocytes were cultured for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatant of RASF and NDSF. Baseline expression was determined of unstimulated chondrocytes. Differential genome-wide microarray analysis of RASF and NDSF stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation (COX-2), NF-kappa B signaling pathway (TLR2), cytokines/chemokines and receptors (CXCL1-3, CCL20, CXCL8, CXCR4, IL-6, IL-1beta), matrix degradation (MMP-10, MMP-12) and suppressed matrix synthesis (COMP). Thus, transcriptome profiling of RASF and NDSF stimulated chondrocytes revealed a disturbed catabolic-anabolic homeostasis of chondrocyte function. This study provides a comprehensive insight into the molecular regulatory processes induced in human chondrocytes during RA-related cartilage destruction. Experiment Overall Design: To reveal the RA-related chondrocyte gene expression profile, genome-wide microarray analysis of RASF stimulated human chondrocytes compared to NDSF stimulation was performed. Unstimulated chondrocytes were analyzed for baseline gene expression. For microarray analysis of RASF and NDSF stimulated and unstimulated chondrocytes, respectively, two RNA pools were analyzed, each pool consisting of equal amounts of RNA from three different donors.
2008-06-11 | E-GEOD-10024 | biostudies-arrayexpress
Project description:Background and aim: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Synovial fibroblasts (SFs) play a key role in the pathogenesis of RA. Dysregulation of MicroRNAs (miRNAs) expression in SFs mediates the development of RA. Exosomes (Exos) can transfer miRNAs between cells and have been validated as carriers for the delivery of therapeutic molecules.This study aimed toinvestigate the therapeutic potential of human umbilical cord mesenchymal stem cells (hUCMSC)-Exos deliveringmiR-451a to regulate ATF2 for RA both in vivo and in vitro. Methods: In this study, hUCMSC and RASF were isolated and identified, and hUCMSC-EXOs were extracted and characterized. The influence of hUCMSC-Exos on RASF was detected. hUCMSC-Exos RNA was labeled and hUCMSC-Exos targeting RA-SFs was traced. AGO2 promoted miRNA maturation, and hUCMSCKD-AGO2 was prepared by knocking down AGO2 in hUCMSC. hUCMSCKD-AGO2-Exos was extracted and characterized,and their influence on RASFs was detected. mRNA and miRNA profiles before and after hUCMSC-Exos intervention in RASFs were mapped to identify differential miRNAs. RT-qPCR was used to verify the differential miRNAs, with miR-451a finally selected as the target gene.The effect of miR-451a on SFs was detected. The latent binding of miR-451a to activating transcription factor 2 (ATF2)was analyzed. The effect of hUCMSC-ExosmiR-451a on SFs was detected, and the expression of miR-451a and ATF2 was measured by RT-PCR.In vivo, hUCMSC-ExosmiR-451a was injected into the ankle joint of CIA rats, and arthritis index, joint imaging and synovial pathology were assessed. The expression of miR-451a and ATF2 in synovial tissue was detected. Finally, the safety of hUCMSC-ExosmiR-451a in CIA rats was evaluated. Results: This study revealed that hUCMSC-Exos can inhibit RASF proliferation, migration and invasion through miRNAs. High throughput sequencing detected 13 miRNAs that could be transmitted from hUCMSC to RASF via hUCMSC-EXOs. MiR-451a inhibited RASF proliferation, migration and invasion by regulating ATF2. hUCMSC-Exos loaded with miR-451a targeted ATF2 to inhibit RASF proliferation, migration and invasion, and improve joint inflammation and imaging findings in CIA rats. Conclusions: This study demonstrates that miR-451a carried by hUCMSC-Exos canplay a role ininhibiting RASF biological traits and improving arthritis in CIA rats by inhibiting ATF2. The findings study suggest a promising treatment for RA and provide insights into the mechanism of action of hUCMSC-Exo in RA.
2025-04-29 | GSE237992 | GEO
Project description:Background and aim: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints. Synovial fibroblasts (SFs) play a key role in the pathogenesis of RA. Dysregulation of MicroRNAs (miRNAs) expression in SFs mediates the development of RA. Exosomes (Exos) can transfer miRNAs between cells and have been validated as carriers for the delivery of therapeutic molecules.This study aimed toinvestigate the therapeutic potential of human umbilical cord mesenchymal stem cells (hUCMSC)-Exos deliveringmiR-451a to regulate ATF2 for RA both in vivo and in vitro. Methods: In this study, hUCMSC and RASF were isolated and identified, and hUCMSC-EXOs were extracted and characterized. The influence of hUCMSC-Exos on RASF was detected. hUCMSC-Exos RNA was labeled and hUCMSC-Exos targeting RA-SFs was traced. AGO2 promoted miRNA maturation, and hUCMSCKD-AGO2 was prepared by knocking down AGO2 in hUCMSC. hUCMSCKD-AGO2-Exos was extracted and characterized,and their influence on RASFs was detected. mRNA and miRNA profiles before and after hUCMSC-Exos intervention in RASFs were mapped to identify differential miRNAs. RT-qPCR was used to verify the differential miRNAs, with miR-451a finally selected as the target gene.The effect of miR-451a on SFs was detected. The latent binding of miR-451a to activating transcription factor 2 (ATF2)was analyzed. The effect of hUCMSC-ExosmiR-451a on SFs was detected, and the expression of miR-451a and ATF2 was measured by RT-PCR.In vivo, hUCMSC-ExosmiR-451a was injected into the ankle joint of CIA rats, and arthritis index, joint imaging and synovial pathology were assessed. The expression of miR-451a and ATF2 in synovial tissue was detected. Finally, the safety of hUCMSC-ExosmiR-451a in CIA rats was evaluated. Results: This study revealed that hUCMSC-Exos can inhibit RASF proliferation, migration and invasion through miRNAs. High throughput sequencing detected 13 miRNAs that could be transmitted from hUCMSC to RASF via hUCMSC-EXOs. MiR-451a inhibited RASF proliferation, migration and invasion by regulating ATF2. hUCMSC-Exos loaded with miR-451a targeted ATF2 to inhibit RASF proliferation, migration and invasion, and improve joint inflammation and imaging findings in CIA rats. Conclusions: This study demonstrates that miR-451a carried by hUCMSC-Exos canplay a role ininhibiting RASF biological traits and improving arthritis in CIA rats by inhibiting ATF2. The findings study suggest a promising treatment for RA and provide insights into the mechanism of action of hUCMSC-Exo in RA.
2025-04-29 | GSE237991 | GEO