Scleraxis: a novel target for anti‐fibrotic therapy?
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Therapeutic approaches to managing cardiac fibrosis are lacking. Our objective is to examine the role of the transcription factor scleraxis (Scx) in cardiac type I collagen production, and to evaluate its potential for anti-fibrotic therapy development. We noted Scx expression in various collagen-producing cell types, including cardiac fibroblasts. Scx expression increases concomitant with collagen production, e.g. in response to TGF-β1 in vitro and in cardiac infarct scar or in pressure-overloaded myocardium in vivo. We have identified sites in the human collagen Iα2 (COLIα2) gene promoter mediating transactivation by scleraxis, and have shown that Scx is sufficient to induce ColIα2 expression in cardiac fibroblasts. Scx expression is regulated by the pro-fibrotic Smad signalling pathway downstream of TGF-β1, which regulates COLIα2 expression additively with Scx. A dominant-negative Scx mutant abrogated TGF-β1-mediated ColIα2 gene expression, suggesting that Scx activity is required for collagen expression in agreement with our finding of reduced cardiac collagen gene expression in Scx null mice. Scx thus plays a central and critical role in collagen expression in the heart, and targeting Scx activity or expression may provide a novel approach in the development of new anti-fibrotic therapies. Supported by the Canadian Institutes of Health Research & the St. Boniface Hospital Research Foundation.Keywords:
Cardiac Fibrosis
Abstract TGF-β1 plays an important role in the pathogenesis of chronic renal diseases. Although the specific mechanism is unknown, a major factor is the potent fibrogenic activity of TGF-β1 in the chronic progression of renal diseases. TGF-β1 closely correlates with renal fibrosis in cooperation with several fibrosis-promoting molecules. Recently it has been studied that, Smad proteins as intracellular mediators of TGF-β signaling pathways provide important insights into the mechanisms determining the specificity of TGF-β action in various renal cells. Some studies have proved that immunosuppressants can affect TGF-β expression, but the mechanisms are unclear. In this study, we investigated the effect of FK506 on mesangial cells via TGF-β and Smads signal pathways. Our results shows that FK506 effectively blocked the TGF-β/Smad signaling pathway by downregulation of TGF-β receptor, and played an important role in TGF-β1-induced Smad2 expression in mice mesangial cells. FK506 can inhibit the TGF-β1-stimulated cell proliferation via Smad-related pathways. And reduced the Smad2 protein and mRNA expression. Altogether, this study provided a theoretical proof for the protective and treating effect of FK506 on kidneys.
Mesangial cell
Pathogenesis
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Background Keloid is a unique proliferative disorder of fibroblasts resulting from derailment of the typical wound healing process. Due to lack of animal models for therapeutic testing, treatment of keloids remains a clinical challenge. Transforming growth factor (TGF)‐β1‐related signalling plays a key role in keloid formation. As tacrolimus (FK506) has been reported to inhibit the effects of TGF‐β1 on cultured fibroblasts, we hypothesized that FK506 may be useful in treating keloids. Objectives To explore the effects of FK506 on TGF‐β1‐stimulated keloid fibroblasts (KFs) in terms of proliferation, migration and collagen production and to investigate the regulatory pathways involved. Methods Fibroblasts derived from keloids were treated with TGF‐β1 with or without FK506. Relevant assays including 5‐bromo‐2′‐deoxyuridine incorporation assay, in vitro scratch assay, reverse transcription–polymerase chain reaction (PCR), quantitative PCR and Western blotting were performed. Results The proliferation and migration of KFs were significantly higher than those of normal fibroblasts. FK506 markedly inhibited KF proliferation, migration and collagen production enhanced by TGF‐β1. The increase in TGF‐β receptor I and II expression in TGF‐β1‐treated KFs was suppressed by FK506 treatment. TGF‐β1 increased the phosphorylation of Smad2/3 and Smad4 in KFs, and this enhancing effect was abrogated by FK506. In addition, FK506 significantly increased the expression of Smad7 which was suppressed by TGF‐β1 treatment. Conclusions Our results demonstrate that FK506 effectively blocks the TGF‐β/Smad signalling pathway in KFs by downregulation of TGF‐β receptors and suggest that FK506 may be included in the armamentarium for treating keloids.
Keloid
Signalling
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MDMX
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Members of transforming growth factor-β(TGF β) superfamily play an important roles in regulating cell growth, differentiation and tissue homeostasis. Smad proteins possess special structure and property and play important roles in transforming growth factor-β(TGF-β) signal transduction pathway. TGF-β activates the downstream Smad proteins,which initiate intracellular signaling pathways via its interaction with TGF-β receptor(TGF-βR) . Research on the varieties,structures and function of Smad proteins,and the complicated regulating mechanism of Smad proteins in TGF-β superfamily signaling transduction are very significative.
Key words:
Transforming growth factor-β; Smad; Signal transduction
R-SMAD
Smad2 Protein
Growth differentiation factor
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Role of transforming growth factor-β/Smad pathway and related factors in the pathogenesis of keloids
摘要： 【摘要】 转化生长因子（TGF）-β/Smad通路在瘢痕疙瘩成纤维细胞的分化和瘢痕疙瘩的疾病进展中起重要作用。在瘢痕疙瘩发病过程中，缺氧诱导因子1α、微小RNA、长链非编码RNA、激活转录因子3、炎症因子、赖氨酸氧化酶样蛋白2等是TGF-β/Smad通路常见的影响因子。本文综述瘢痕疙瘩发病机制中TGF-β/Smad通路和常见影响因子的最新研究进展。
Pathogenesis
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R-SMAD
Smad2 Protein
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Objective:To observe the proliferation of JEG-3 choriocarcinoma cells and Smad 3,7 mRNA expression changes under the action of transforming growth factor β1(TGF-β1),explore the mechanism of TGF-β/Smads signal channel in occurrence and development of choriocarcinoma.Methods:The JEG-3 choriocarcinoma cells were treated with different concentrations and times of TGF-β1,the cell proliferation activity was detected by MTT method,the difference of Smad 3,7 mRNA expression was detected by RT-PCR.Results:TGF-β1 stimulated the proliferation of JEG-3 choriocarcinoma cell;the expression level of Smad 3 mRNA gradually increased with the increase of TGF-β1 concentration;after treated with a certain concentration of TGF-β1 for 12 hours,the expression level of Smad 3 mRNA gradually increased with time passing;under the same condition,there was no significant difference in expression level of Smad 7.Conclusion:TGF-β1 can stimulates the proliferation of JEG-3 choriocarcinoma cell;the reaction of Smad 3 mRNA to exogenous TGF-β1 is good,while Smad 7 mRNA has no response.
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As a crucial regulatory molecule in the context of vascular stenosis, transforming growth factor-β (TGF-β), plays a pivotal role in its initiation and progression. TGF-β, a member of the TGF-β superfamily, can bind to the TGF-β receptor and transduce extracellular to intracellular signals through canonical Smad dependent or noncanonical signaling pathways to regulate cell growth, proliferation, differentiation, and apoptosis. Restenosis remains one of the most challenging problems in cardiac, cerebral, and peripheral vascular disease worldwide. The mechanisms for occurrence and development of restenosis are diverse and complex. The TGF-β pathway exhibits diversity across various cell types. Hence, clarifying the specific roles of TGF-β within different cell types and its precise impact on vascular stenosis provides strategies for future research in the field of stenosis.
R-SMAD
Smad2 Protein
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Posterior capsule opacification (PCO) is the frequent complication after cataract surgery.Transforming growth factor-β (TGF-β) is the important growth factor to modulate the transdifferentiation and formation of extracellular cell matrix (ECM) of cells.TGF-β modulates the proliferation,epithelial-mesenchymal transition and the formation of ECM by Smad signaling pathway.The research progress of TGF-β/Smad signaling pathway in PCO is reviewed in this article.
Transdifferentiation
Smad2 Protein
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Cardiac Fibrosis
Myocardial fibrosis
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