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  • 1
    Online-Ressource
    Online-Ressource
    Identification and functional characterization of imbalanced osteoarthritis-associated fibronectin splice variants
    Oxford University Press (OUP) ; 2023
    In:  Rheumatology Vol. 62, No. 2 ( 2023-02-01), p. 894-904
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 62, No. 2 ( 2023-02-01), p. 894-904
    Kurzfassung: To identify FN1 transcripts associated with OA pathophysiology and investigate the downstream effects of modulating FN1 expression and relative transcript ratio. Methods FN1 transcriptomic data was obtained from our previously assessed RNA-seq dataset of lesioned and preserved OA cartilage samples from the Research osteoArthritis Articular Cartilage (RAAK) study. Differential transcript expression analysis was performed on all 27 FN1 transcripts annotated in the Ensembl database. Human primary chondrocytes were transduced with lentiviral particles containing short hairpin RNA (shRNA) targeting full-length FN1 transcripts or non-targeting shRNA. Subsequently, matrix deposition was induced in our 3D in vitro neo-cartilage model. Effects of changes in the FN1 transcript ratio on sulphated glycosaminoglycan (sGAG) deposition were investigated by Alcian blue staining and dimethylmethylene blue assay. Moreover, gene expression levels of 17 cartilage-relevant markers were determined by reverse transcription quantitative polymerase chain reaction. Results We identified 16 FN1 transcripts differentially expressed between lesioned and preserved cartilage. FN1-208, encoding migration-stimulating factor, was the most significantly differentially expressed protein coding transcript. Downregulation of full-length FN1 and a concomitant increased FN1-208 ratio resulted in decreased sGAG deposition as well as decreased ACAN and COL2A1 and increased ADAMTS-5, ITGB1 and ITGB5 gene expression levels. Conclusion We show that full-length FN1 downregulation and concomitant relative FN1-208 upregulation was unbeneficial for deposition of cartilage matrix, likely due to decreased availability of the classical RGD (Arg-Gly-Asp) integrin-binding site of fibronectin.
    Materialart: Online-Ressource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keac272
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2023
    ZDB Id: 1474143-X
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Long non-coding RNA expression profiling of subchondral bone reveals AC005165.1 modifying FRZB expression during osteoarthritis
    Oxford University Press (OUP) ; 2022
    In:  Rheumatology Vol. 61, No. 7 ( 2022-07-06), p. 3023-3032
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 61, No. 7 ( 2022-07-06), p. 3023-3032
    Kurzfassung: To gain insight in the expression profile of long non-coding RNAs (lncRNAs) in OA subchondral bone. Methods RNA sequencing data of macroscopically preserved and lesioned OA subchondral bone of patients that underwent joint replacement surgery due to OA (N = 22 pairs; 5 hips, 17 knees, Research osteoArthrits Articular Tissue (RAAK study) was run through an in-house pipeline to detect expression of lncRNAs. Differential expression analysis between preserved and lesioned bone was performed. Spearman correlations were calculated between differentially expressed lncRNAs and differentially expressed mRNAs identified previously in the same samples. Primary osteogenic cells were transfected with locked nucleic acid (LNA) GapmeRs targeting AC005165.1 lncRNA, to functionally investigate its potential mRNA targets. Results In total, 2816 lncRNAs were well-expressed in subchondral bone and we identified 233 lncRNAs exclusively expressed in knee and 307 lncRNAs exclusively in hip. Differential expression analysis, using all samples (N = 22 pairs; 5 hips, 17 knees), resulted in 21 differentially expressed lncRNAs [false discovery rate (FDR) & lt; 0.05, fold change (FC) range 1.19–7.39], including long intergenic non-protein coding RNA (LINC) 1411 (LINC01411, FC = 7.39, FDR = 2.20 × 10−8), AC005165.1 (FC = 0.44, FDR = 2.37 × 10−6) and empty spiracles homeobox 2 opposite strand RNA (EMX2OS, FC = 0.41, FDR = 7.64 × 10−3). Among the differentially expressed lncRNAs, five were also differentially expressed in articular cartilage, including AC005165.1, showing similar direction of effect. Downregulation of AC005165.1 in primary osteogenic cells resulted in consistent downregulation of highly correlated frizzled related protein (FRZB). Conclusion The current study identified a novel lncRNA, AC005165.1, being dysregulated in OA articular cartilage and subchondral bone. Downregulation of AC005165.1 caused a decreased expression of OA risk gene FRZB, an important member of the wnt pathway, suggesting that AC005165.1 could be an attractive potential therapeutic target with effects in articular cartilage and subchondral bone.
    Materialart: Online-Ressource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keab826
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2022
    ZDB Id: 1474143-X
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Inhibiting thyroid activation in aged human explants prevents mechanical induced detrimental signalling by mitigating metabolic processes
    Oxford University Press (OUP) ; 2022
    In:  Rheumatology Vol. 62, No. 1 ( 2022-12-23), p. 457-466
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 62, No. 1 ( 2022-12-23), p. 457-466
    Kurzfassung: To investigate whether the deiodinase inhibitor iopanoic acid (IOP) has chondroprotective properties, a mechanical stress induced model of human aged explants was used to test both repeated dosing and slow release of IOP. Methods Human osteochondral explants subjected to injurious mechanical stress (65%MS) were treated with IOP or IOP encapsulated in poly lactic-co-glycolic acid–polyethylene glycol nanoparticles (NP-IOP). Changes to cartilage integrity and signalling were determined by Mankin scoring of histology, sulphated glycosaminoglycan (sGAG) release and expression levels of catabolic, anabolic and hypertrophic markers. Subsequently, on a subgroup of samples, RNA sequencing was performed on 65%MS (n = 14) and 65%MS+IOP (n = 7) treated cartilage to identify IOP’s mode of action. Results Damage from injurious mechanical stress was confirmed by increased cartilage surface damage in the Mankin score, increased sGAG release, and consistent upregulation of catabolic markers and downregulation of anabolic markers. IOP and, though less effective, NP-IOP treatment, reduced MMP13 and increased COL2A1 expression. In line with this, IOP and NP-IOP reduced cartilage surface damage induced by 65%MS, while only IOP reduced sGAG release from explants subjected to 65%MS. Lastly, differential expression analysis identified 12 genes in IOP’s mode of action to be mainly involved in reducing metabolic processes (INSIG1, DHCR7, FADS1 and ACAT2) and proliferation and differentiation (CTGF, BMP5 and FOXM1). Conclusion Treatment with the deiodinase inhibitor IOP reduced detrimental changes of injurious mechanical stress. In addition, we identified that its mode of action was likely on metabolic processes, cell proliferation and differentiation.
    Materialart: Online-Ressource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keac202
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2022
    ZDB Id: 1474143-X
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage
    BMJ ; 2019
    In:  Annals of the Rheumatic Diseases Vol. 78, No. 2 ( 2019-02), p. 270-277
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 78, No. 2 ( 2019-02), p. 270-277
    Kurzfassung: To uncover the microRNA (miRNA) interactome of the osteoarthritis (OA) pathophysiological process in the cartilage. Methods We performed RNA sequencing in 130 samples (n=35 and n=30 pairs for messenger RNA (mRNA) and miRNA, respectively) on macroscopically preserved and lesioned OA cartilage from the same patient and performed differential expression (DE) analysis of miRNA and mRNAs. To build an OA-specific miRNA interactome, a prioritisation scheme was applied based on inverse Pearson’s correlations and inverse DE of miRNAs and mRNAs. Subsequently, these were filtered by those present in predicted (TargetScan/microT-CDS) and/or experimentally validated (miRTarBase/TarBase) public databases. Pathway enrichment analysis was applied to elucidate OA-related pathways likely mediated by miRNA regulatory mechanisms. Results We found 142 miRNAs and 2387 mRNAs to be differentially expressed between lesioned and preserved OA articular cartilage. After applying prioritisation towards likely miRNA-mRNA targets, a regulatory network of 62 miRNAs targeting 238 mRNAs was created. Subsequent pathway enrichment analysis of these mRNAs (or genes) elucidated that genes within the ‘nervous system development’ are likely mediated by miRNA regulatory mechanisms (familywise error=8.4×10 −5 ). Herein NTF3 encodes neurotrophin-3, which controls survival and differentiation of neurons and which is closely related to the nerve growth factor. Conclusions By an integrated approach of miRNA and mRNA sequencing data of OA cartilage, an OA miRNA interactome and related pathways were elucidated. Our functional data demonstrated interacting levels at which miRNA affects expression of genes in the cartilage and exemplified the complexity of functionally validating a network of genes that may be targeted by multiple miRNAs.
    Materialart: Online-Ressource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2018-213882
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: BMJ
    Publikationsdatum: 2019
    ZDB Id: 1481557-6
    Standort Signatur Einschränkungen Verfügbarkeit
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    Online-Ressource
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