The Mighty Fibroblast and Its Utility in Scleroderma Research

Garrett, Steven L.; Frost, DeAnna Baker; Feghali‐Bostwick, Carol

doi:10.5301/jsrd.5000240

Cited by 65 publications

(68 citation statements)

References 95 publications

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“…Under physiologic conditions, this process is terminated by reparative mechanisms driving the myofibroblasts into apoptosis. In the pathologic course of SSc, persistent TGFβ1 signaling protects myofibroblasts against apoptosis and facilitates fibrosis .…”

Section: Introductionmentioning

confidence: 99%

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA‐125b in Systemic Sclerosis

Kozlova

Pachera

Maurer

et al. 2019

Arthritis & Rheumatology

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Objective. To analyze the expression, regulation, and role of microRNA-125b (miR-125b) in systemic sclerosis (SSc).Methods. MiR-125b expression was assessed by quantitative polymerase chain reaction (qPCR) of RNA from dermal fibroblasts and whole skin biopsy specimens from healthy controls and SSc patients. To identify downstream effectors, RNA from healthy control fibroblasts was sequenced after miR-125b knockdown and further validated using qPCR and Western blotting. Fibrosis, apoptosis, and proliferation were assessed by Caspase-Glo 3/7 assay, Western blotting, immunofluorescence staining for cleaved caspase 3, and annexin V real-time assay in dermal fibroblasts.Results. Expression of miR-125b was significantly down-regulated in SSc skin biopsy specimens by 53% (median fold change 0.47 [interquartile range 0.35-0.69]; P < 0.001) and in SSc dermal fibroblasts by 47% (median fold change 0.53 [interquartile range 0.36-0.58]; P < 0.001) compared to healthy control skin biopsy specimens and fibroblasts, respectively (n = 10 samples per group). Treatment with the histone deacetylase inhibitors trichostatin A and tubastatin A significantly decreased the expression of miR-125b in dermal fibroblasts. MiR-125b knockdown significantly reduced cell proliferation and α-smooth muscle actin (α-SMA) expression at the messenger RNA (mRNA) and protein levels. RNA-Seq identified BAK1, BMF, and BBC3 as potential targets of miR-125b. Quantitative PCR confirmed that knockdown of miR-125b up-regulated these genes (P < 0.01; n = 12). Bcl-2 homologous antagonist killer 1 showed the strongest induction confirmed at the protein level (P < 0.01; n = 10). Consequently, miR-125b knockdown increased apoptosis compared to scrambled control. Accordingly, miR-125b overexpression decreased apoptosis.Conclusion. Our findings indicate that miR-125b is down-regulated in SSc skin and primary dermal fibroblasts. MiR-125b down-regulation increases apoptosis and decreases proliferation and α-SMA expression in dermal fibroblasts, indicating that its compensatory, antifibrotic mechanism may be a potential novel therapeutic option.

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Section: Introductionmentioning

confidence: 99%

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA‐125b in Systemic Sclerosis

Kozlova

Pachera

Maurer

et al. 2019

Arthritis & Rheumatology

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“…Systemic sclerosis (SSc), or scleroderma, is a complex multisystem autoimmune disease characterized by vascular injury, inflammation, and accumulation of excessive extracellular matrix (ECM) protein, ultimately resulting in fibrosis of the dermal and internal organs, including the lungs, the gastrointestinal tract, and the heart [1][2][3][4]. Although the exact etiology and precise mechanism driving this disease remain largely elusive, accumulating evidence has shown that the transforming growth factor β (TGF-β) pathway may be the most important factor in the pathogenesis of SSc [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor

Shi

Liu

et al. 2018

Cell Cycle

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Systemic sclerosis (SSc) is a multisystemic fibrotic disease characterized by excessive collagen deposition and extracellular matrix synthesis. Though transforming growth factor-β (TGF-β) plays a fundamental role in the pathogenesis of SSc, the mechanism by which TGF-β signaling acts in SSc remains largely unclear. Here, we showed that TGF-β type II receptor (TGFBR2) was significantly upregulated in both human SSc dermal tissues and primary fibroblasts. In fibroblasts, siRNA-induced knockdown of TGFBR2 resulted in a reduction of p-SMAD2/3 levels and reduced production of type I collagen. Additionally, functional experiments revealed that downregulation of TGFBR2 yielded an anti-growth effect on fibroblasts through inhibiting cell cycle progression. Further studies showed that miR-3606-3p could directly target the 3'-UTR of TGFBR2 and significantly decrease the levels of both TGFBR2 mRNA and protein. Furthermore, SSc dermal tissues and primary fibroblasts contain significantly reduced amounts of miR-3606-3p, and the overexpression of miR-3606-3p in fibroblasts replicates the phenotype of TGFBR2 downregulation. Collectively, our findings demonstrated that increased TGFBR2 could be responsible for the hyperactive TGF-β signaling observed in SSc. Moreover, we identified a pivotal role for miR-3606-3p in SSc, which acts, at least partly, through the attenuation of TGF-β signaling via TGFBR2 repression, suggesting that the regulation of miR-3606-3p/TGFBR2 could be a promising therapeutic target that could improve the treatment strategy for fibrosis.

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“…Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc. 1 Fb stimulation with TGF-b1 is usually considered as the positive control in studies assessing the fibrogenesis in SSc. 2 Yet, the lack of standardisation of TGF-b1 stimulation might be responsible for discrepancies in experiments performed in different conditions.…”

mentioning

confidence: 99%

AB0194 Sparc is elevated in the affected skin of systemic sclerosis patients and induces the expression of fibrotic genes in dermal fibroblasts and macrophages

Pérez

Fernández

Bergin³

et al. 2018

Systemic Sclerosis, Myositis and Related Syndromes – Etiology, Pathogenesis and Animal Models

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BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterised by inflammation, vascular injury and excessive fibrosis in multiple organs. SPARC is a matricellular glycoprotein that can bind to extracellular matrix (ECM) components, as well as cellular receptors and secreted growth factors. In doing so, SPARC regulates biological activities dependent upon cellular interactions with the ECM as well as processes dependent upon cell adhesion, including tissue remodelling, wound healing, angiogenesis and immune responses. Several studies have implicated SPARC in the pathology of SSc but the specific role of SPARC in fibrosis is still unknown.ObjectivesThe aim of this study was to analyse the potential role of SPARC as a regulator of fibrosis in SSc.MethodsExpression of SPARC in the skin of healthy donors (HD) and SSc patients was measured by immunohistochemistry. Peripheral blood-derived monocytes from HD and SSc patients were differentiated into macrophages with M-CSF (25 ng/ml). Dermal fibroblasts and M-CSF macrophages from both HD and SSc patients were stimulated with SPARC (0.1 and 1 µg/ml) for 6 hour and 24 hour. mRNA and protein expression of SPARC and other fibrosis-related genes were measured by qPCR and western blot.ResultsWe found increased expression of SPARC in the affected skin of SSc patients compared to HD. We also observed a higher expression of SPARC and ECM components (colagen(Col)−1 and fibronectin-1 (FN1) in dermal fibroblasts derived from SSc patients. SPARC stimulation induced mRNA expression of important fibrosis-related genes such as TGFB1, PDGFB, SERPINE1 and CTGF, and ECM components including COL1A1, COL3A1, COL4A1 and FN1 in dermal fibroblasts from SSc patients, but not healthy donors. In M-CSF macrophages from SSc patients, SPARC also up-regulated mRNA expression of TGFB1, PDGFB, STAB1,COL1A1 and FN1.ConclusionsThese results suggest that SPARC is an important pro-fibrotic mediator contributing to the pathology driving SSc. Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc.Disclosure of InterestS. García Pérez: None declared, B. Malvar Fernández: None declared, M. Bergin Employee of: UCB, T. Johnson Employee of: UCB, W. Marut: None declared, K. A. Reedquist: None declared, T. R. Radstake: None declared

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The Mighty Fibroblast and Its Utility in Scleroderma Research

Cited by 65 publications

References 95 publications

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA‐125b in Systemic Sclerosis

Regulation of Fibroblast Apoptosis and Proliferation by MicroRNA‐125b in Systemic Sclerosis

MiR-3606-3p inhibits systemic sclerosis through targeting TGF-β type II receptor

AB0194 Sparc is elevated in the affected skin of systemic sclerosis patients and induces the expression of fibrotic genes in dermal fibroblasts and macrophages

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