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  • Simonds, Megan M.  (6)
  • 1
    Online Resource
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    Prior to extension, Transcriptomes of fibroblast-like Synoviocytes from extended and Polyarticular juvenile idiopathic arthritis are indistinguishable
    Springer Science and Business Media LLC ; 2018
    In:  Pediatric Rheumatology Vol. 16, No. 1 ( 2018-12)
    Details
    In: Pediatric Rheumatology, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2018-12)
    Type of Medium: Online Resource
    ISSN: 1546-0096
    URL: Article
    DOI: 10.1186/s12969-017-0217-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2279468-2
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  • 2
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    Juvenile idiopathic arthritis fibroblast-like synoviocytes influence chondrocytes to alter BMP antagonist expression demonstrating an interaction between the two prominent cell types involved in endochondral bone formation
    Springer Science and Business Media LLC ; 2020
    In:  Pediatric Rheumatology Vol. 18, No. 1 ( 2020-12)
    Details
    In: Pediatric Rheumatology, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2020-12)
    Abstract: To examine critical interactions between juvenile idiopathic arthritis synovial fibroblasts (JFLS) and chondrocytes (Ch), and their role in bony overgrowth seen in patients with juvenile idiopathic arthritis (JIA). Methods Control (CFLS) and JFLS were cultured in synoviocyte media containing recombinant BMP4. Ch were cultured in either CFLS or JFLS conditioned-media without stimulation. Media supernatants were analyzed by ELISA. RNA from conditioned media experiment was analyzed by ClariomS microarray. Results As expected, genes expressed in untreated JFLS and CFLS cultured in synoviocyte media were similar to each other and this expression differed from untreated Ch cultured in chondrocyte media. JFLS favor BMP ligand gene expression while downregulating TGFβ receptors’ expression. Noggin and chordin, antagonists with high affinity for BMP4, are JFLS- but not Ch-preferred regulators of BMP signaling. Compared to Ch, JFLS overexpress collagen X (COLX), a marker of chondrocyte hypertrophy. Exogenous BMP4 causes JFLS to significantly decrease expression of noggin and collagen II (COL2), a marker of chondrocyte proliferation, and causes overexpression of COLX and alkaline-phosphatase (ALP). Chondrocytes cultured in JFLS-conditioned media (Ch-JFLS) express BMP genes and favor chordin protein expression over other antagonists. Ch-JFLS have significantly increased expression of COL2 and significantly decreased expression of COLX. Conclusions These data suggest JFLS, in the presence of BMP4, undergo hypertrophy and that JFLS-conditioned media influence chondrocytes to become highly proliferative. To the authors’ knowledge, no prior study has shown that JFLS and chondrocytes play a direct role in the bony overgrowth in joints of patients with JIA and that BMPs or regulation of these growth factors influence the interaction between two prominent synovial cell types.
    Type of Medium: Online Resource
    ISSN: 1546-0096
    URL: Article
    DOI: 10.1186/s12969-020-00483-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2279468-2
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  • 3
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    The Role of Transforming Growth Factor β Signaling in Fibroblast‐like Synoviocytes From Patients With Oligoarticular Juvenile Idiopathic Arthritis: Dysregulation of Transforming Growth Factor β Signaling, Including Overexpression of Bone Morphogenetic Protein 4, May Lead to a Chondrocyte Phenotype and May Contribute to Bony Hypertrophy
    Wiley ; 2014
    In:  Arthritis & Rheumatology Vol. 66, No. 5 ( 2014-05), p. 1352-1362
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 66, No. 5 ( 2014-05), p. 1352-1362
    Abstract: This study was designed to investigate the pathogenic contributions of fibroblast‐like synoviocytes (FLS) to juvenile idiopathic arthritis (JIA) by identifying pathways with dysregulated gene expression in FLS from patients with oligoarticular JIA. Methods FLS were derived from synovial fluid obtained by arthrocentesis from patients with JIA undergoing intraarticular steroid injections and from orthopedic control patients. Gene expression profiles of the JIA and control FLS were obtained using the Affymetrix platform, with application of Ingenuity Pathway Analysis and Gene Set Enrichment Analysis software to define gene sets in dysregulated pathways and networks of potential pathologic relevance in this disease. Biologically relevant differentially expressed genes were confirmed by RNA and protein analysis. Results Exploration of global gene expression profiles of the JIA FLS revealed important dysregulated pathways, including the transforming growth factor β (TGFβ) signaling, as well as endochondral bone formation, cartilage formation, and β‐catenin networks. Importantly, bone morphogenetic protein 4 (BMP‐4) was significantly overexpressed in the JIA FLS. FLS from patients with oligoarticular JIA exhibit a chondrocyte phenotype, as evidenced by expression of type II collagen and aggrecan. Conclusion Dysregulation of the pathways involved in the pathogenesis of oligoarticular JIA were revealed through gene expression profiling. JIA FLS displayed dysregulated TGFβ signaling and exhibited a hypertrophic chondrocyte phenotype. These characteristics, along with contributions from the β‐catenin network may have implications for endochondral bone formation and local growth disturbances in oligoarticular JIA. Overexpression of BMP‐4 in FLS from patients with oligoarticular JIA in particular may play an important role in disease pathogenesis, with a direct effect on functional outcome and with implications for future treatment.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v66.5
    DOI: 10.1002/art.38336
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2754614-7
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  • 4
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    The culture microenvironment of juvenile idiopathic arthritis synovial fibroblasts is favorable for endochondral bone formation through BMP4 and repressed by chondrocytes
    Springer Science and Business Media LLC ; 2021
    In:  Pediatric Rheumatology Vol. 19, No. 1 ( 2021-12)
    Details
    In: Pediatric Rheumatology, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2021-12)
    Abstract: We examined influences of conditioned media from chondrocytes (Ch) on juvenile idiopathic arthritis synovial fibroblasts (JFLS) and potential for JFLS to undergo endochondral bone formation (EBF). Methods Primary cells from three control fibroblast-like synoviocytes (CFLS) and three JFLS were cultured in Ch-conditioned media and compared with untreated fibroblast-like synoviocytes (FLS). RNA was analyzed by ClariomS microarray. FLS cells cultured in conditioned media were exposed to either TGFBR1 inhibitor LY3200882 or exogenous BMP4 and compared with FLS cultured in conditioned media from Ch (JFLS-Ch). Media supernatants were analyzed by ELISA. Results In culture, JFLS downregulate BMP2 and its receptor BMPR1a while upregulating BMP antagonists (NOG and CHRD) and express genes (MMP9, PCNA, MMP12) and proteins (COL2, COLX, COMP) associated with chondrocytes. Important TGFβ superfamily member gene expression (TGFBI, MMP9, COL1A1, SOX6, and MMP2) is downregulated when JFLS are cultured in Ch-conditioned media. COL2, COLX and COMP protein expression decreases in JFLS-Ch. BMP antagonist protein (NOG, CHRD, GREM, and FST) secretion is significantly increased in JFLS-Ch. Protein phosphorylation increases in JFLS-Ch exposed to exogenous BMP4, and chondrocyte-like phenotype is restored in BMP4 presence, evidenced by increased secretion of COL2 and COLX. Inhibition of TGFBR1 in JFLS-Ch results in overexpression of COL2. Conclusions JFLS are chondrocyte-like, and Ch-conditioned media can abrogate this phenotype. The addition of exogenous BMP4 causes JFLS-Ch to restore this chondrocyte-like phenotype, suggesting that JFLS create a microenvironment favorable for endochondral bone formation, thereby contributing to joint growth disturbances in juvenile idiopathic arthritis.
    Type of Medium: Online Resource
    ISSN: 1546-0096
    URL: Article
    DOI: 10.1186/s12969-021-00556-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2279468-2
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  • 5
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    Secretion of pro‐inflammatory cytokines and chemokines and loss of regulatory signals by fibroblast‐like synoviocytes in juvenile idiopathic arthritis
    Wiley ; 2017
    In:  PROTEOMICS – Clinical Applications Vol. 11, No. 5-6 ( 2017-05)
    Details
    In: PROTEOMICS – Clinical Applications, Wiley, Vol. 11, No. 5-6 ( 2017-05)
    Abstract: The goal is to investigate the specific contribution of fibroblast‐like synoviocytes (FLS) to the inflammatory milieu of the synovium in juvenile idiopathic arthritis (JIA) through detection of secreted proteins. Experimental design Expression of 89 cytokines and chemokines is determined on unprocessed synovial fluid from controls and JIA patients using antibody arrays. Supernatants from pure cell cultures of FLS grown from synovial fluids or tissues from JIA and controls are also examined for protein expression. Ingenuity Pathway Analysis (IPA) is revealed top pathways and upstream regulators of significant proteins. Results Protein studies is revealed that JIA FLS release pro‐inflammatory cytokines and chemokines, including IL‐4, IL‐6, IL‐17, CXCL1, and CXCL6, and lose expression of important regulator signals, such as IL‐10 and TIMP2. Of the 84 proteins differentially expressed between controls and JIA in the synovial fluid, 1/3 (29 proteins) are differentially expressed in the cell culture supernatants of JIA and control FLS. ELISA of cell culture supernatants and synovial fluid confirmed seven key proteins. Conclusion and clinical relevance JIA FLS are central to perpetuation of inflammation in JIA, including trafficking of inflammatory cells and effects on the extracellular matrix. These cells express key disease‐specific chemokines that, with further refinement, may allow us to tailor therapy appropriately.
    Type of Medium: Online Resource
    ISSN: 1862-8346 , 1862-8354
    URL: Issue
    URL: Article
    DOI: 10.1002/prca.v11.5-6
    DOI: 10.1002/prca.201600088
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2317130-3
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  • 6
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    Single-cell analysis reveals heterogeneity of juvenile idiopathic arthritis fibroblast-like synoviocytes with implications for disease subtype
    Springer Science and Business Media LLC ; 2022
    In:  Arthritis Research & Therapy Vol. 24, No. 1 ( 2022-09-27)
    Details
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 24, No. 1 ( 2022-09-27)
    Abstract: Fibroblast-like synoviocytes (FLS) play a crucial role in JIA pathogenesis; however, the mechanisms by which they contribute to disease progression are not well described. Previous studies demonstrated that rheumatoid arthritis FLS are heterogeneous, and subpopulations with transformed, aggressive phenotypes cause invasive and destructive disease activity. We employ single-cell RNA-sequencing (scRNA-seq) to investigate JIA FLS heterogeneity and gene expression that distinguishes JIA subtypes. Methods JIA FLS cell lines from three persistent oligoarticular, three pre-extension oligoarticular, and three polyarticular subtypes were cultured. scRNA-seq was performed by Genewiz according to 10 × Genomics Chromium protocols. SeuratR package was used for QC, analysis, and exploration of data. Results FLS are heterogeneous and have characteristics of fibroblasts, chondrocytes, and smooth muscle cells. The chondrocyte-like subpopulation is the predominant cell type and percentages of this subpopulation increase with disease severity. Despite overlapping subpopulations, the chondrocyte-like cells have unique genetic fingerprints that distinguish between JIA subtypes. LRRC15, GREM1, and GREM2 are overexpressed in chondrocyte-like cells from persistent oligoarticular JIA FLS compared to pre-extension oligoarticular JIA FLS. S100A4, TIMP3, and NBL1 are overexpressed in pre-extension oligoarticular JIA FLS compared to polyarticular JIA FLS. CRLF1, MFAP5, and TNXB are overexpressed in persistent oligoarticular JIA FLS compared to polyarticular JIA FLS. Conclusions We found biologically relevant differences in gene expression between JIA subtypes that support a critical role for FLS in pathogenesis. We also demonstrate that gene expression within the chondrocyte-like subpopulation can be used to distinguish between these subtypes.
    Type of Medium: Online Resource
    ISSN: 1478-6362
    URL: Article
    DOI: 10.1186/s13075-022-02913-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041668-4
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