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  • 1
    Online Resource
    Online Resource
    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
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keab826
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474143-X
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  • 2
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    RNA Sequencing Reveals Interacting Key Determinants of Osteoarthritis Acting in Subchondral Bone and Articular Cartilage: Identification of IL11 and CHADL as Attractive Treatment Targets
    Wiley ; 2021
    In:  Arthritis & Rheumatology Vol. 73, No. 5 ( 2021-05), p. 789-799
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 73, No. 5 ( 2021-05), p. 789-799
    Abstract: To identify key determinants of the interactive pathophysiologic processes in subchondral bone and cartilage in osteoarthritis (OA). Methods We performed RNA sequencing on macroscopically preserved and lesional OA subchondral bone from patients in the Research Arthritis and Articular Cartilage study who underwent joint replacement surgery due to OA (n = 24 sample pairs: 6 hips and 18 knees). Unsupervised hierarchical clustering and differential expression analyses were conducted. Results were combined with data on previously identified differentially expressed genes in cartilage (partly overlapping samples) as well as data on recently identified OA risk genes. Results We identified 1,569 genes that were significantly differentially expressed between lesional and preserved subchondral bone, including CNTNAP2 (fold change [FC] 2.4, false discovery rate [FDR] 3.36 × 10 −5 ) and STMN2 (FC 9.6, FDR 2.36 × 10 −3 ). Among these 1,569 genes, 305 were also differentially expressed, and with the same direction of effect, in cartilage, including the recently recognized OA susceptibility genes IL11 and CHADL . Upon differential expression analysis with stratification for joint site, we identified 509 genes that were exclusively differentially expressed in subchondral bone of the knee, including KLF11 and WNT4 . These genes that were differentially expressed exclusively in the knee were enriched for involvement in epigenetic processes, characterized by, e.g., HIST1H3J and HIST1H3H . Conclusion IL11 and CHADL were among the most consistently differentially expressed genes OA pathophysiology–related genes in both bone and cartilage . As these genes were recently also identified as robust OA risk genes, they classify as attractive therapeutic targets acting on 2 OA‐relevant tissues.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v73.5
    DOI: 10.1002/art.41600
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2754614-7
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  • 3
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    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
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keac272
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474143-X
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  • 4
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    Online Resource
    Elucidating Epigenetic Regulation by Identifying Functional cis ‐Acting Long Noncoding RNAs and Their Targets in Osteoarthritic Articular Cartilage
    Wiley ; 2020
    In:  Arthritis & Rheumatology Vol. 72, No. 11 ( 2020-11), p. 1845-1854
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 72, No. 11 ( 2020-11), p. 1845-1854
    Abstract: To identify robustly differentially expressed long noncoding RNAs (lncRNAs) with osteoarthritis (OA) pathophysiology in cartilage and to explore potential target messenger RNA (mRNA) by establishing coexpression networks, followed by functional validation. Methods RNA sequencing was performed on macroscopically lesioned and preserved OA cartilage from patients who underwent joint replacement surgery due to OA (n = 98). Differential expression analysis was performed on lncRNAs that were annotated in GENCODE and Ensembl databases. To identify potential interactions, correlations were calculated between the identified differentially expressed lncRNAs and the previously reported differentially expressed protein‐coding genes in the same samples. Modulation of chondrocyte lncRNA expression was achieved using locked nucleic acid GapmeRs. Results By applying our in‐house pipeline, we identified 5,053 lncRNAs that were robustly expressed, of which 191 were significantly differentially expressed (according to false discovery rate) between lesioned and preserved OA cartilage. Upon integrating mRNA sequencing data, we showed that intergenic and antisense differentially expressed lncRNAs demonstrate high, positive correlations with their respective flanking sense genes. To functionally validate this observation, we selected P3H2‐AS1 , which was down‐regulated in primary chondrocytes, resulting in the down‐regulation of P3H2 gene expression levels. As such, we can confirm that P3H2‐AS1 regulates its sense gene P3H2 . Conclusion By applying an improved detection strategy, robustly differentially expressed lncRNAs in OA cartilage were detected. Integration of these lncRNAs with differential mRNA expression levels in the same samples provided insight into their regulatory networks. Our data indicate that intergenic and antisense lncRNAs play an important role in regulating the pathophysiology of OA.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v72.11
    DOI: 10.1002/art.41396
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2754614-7
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  • 5
    Online Resource
    Online Resource
    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
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2018-213882
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 1481557-6
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