TGF-β in fibrosis by acting as a conductor for contractile properties of myofibroblasts

Vallée, Alexandre; Lecarpentier, Yves

doi:10.1186/s13578-019-0362-3

Cited by 119 publications

(102 citation statements)

References 161 publications

(195 reference statements)

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“…A recognized molecular driver of fibrosis is the TGFβ signalling pathway. TGFβ drives the conversion of fibroblasts to myofibroblasts to induce the excessive deposition of collagen and inappropriate ECM during fibrosis, recently reviewed in [127]. Generic molecular markers for myofibroblasts are similar to markers for smooth muscle cells, such as Acta2 (smooth muscle actin), whose expression is regulated by TGFβ signalling [127].…”

Section: Egr1 Is a Fibrotic Factormentioning

confidence: 99%

“…TGFβ drives the conversion of fibroblasts to myofibroblasts to induce the excessive deposition of collagen and inappropriate ECM during fibrosis, recently reviewed in [127]. Generic molecular markers for myofibroblasts are similar to markers for smooth muscle cells, such as Acta2 (smooth muscle actin), whose expression is regulated by TGFβ signalling [127]. Although myofibroblasts and TGFβ are recognized to be the respective cellular and molecular hallmarks of fibrosis, there is no comprehensive understanding of the cellular and molecular mechanisms underlying fibrosis.…”

Section: Egr1 Is a Fibrotic Factormentioning

confidence: 99%

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EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Havis

Duprez

2020

IJMS

363

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Although the transcription factor EGR1 is known as NGF1-A, TIS8, Krox24, zif/268, and ZENK, it still has many fewer names than biological functions. A broad range of signals induce Egr1 gene expression via numerous regulatory elements identified in the Egr1 promoter. EGR1 is also the target of multiple post-translational modifications, which modulate EGR1 transcriptional activity. Despite the myriad regulators of Egr1 transcription and translation, and the numerous biological functions identified for EGR1, the literature reveals a recurring theme of EGR1 transcriptional activity in connective tissues, regulating genes related to the extracellular matrix. Egr1 is expressed in different connective tissues, such as tendon (a dense connective tissue), cartilage and bone (supportive connective tissues), and adipose tissue (a loose connective tissue). Egr1 is involved in the development, homeostasis, and healing processes of these tissues, mainly via the regulation of extracellular matrix. In addition, Egr1 is often involved in the abnormal production of extracellular matrix in fibrotic conditions, and Egr1 deletion is seen as a target for therapeutic strategies to fight fibrotic conditions. This generic EGR1 function in matrix regulation has little-explored implications but is potentially important for tendon repair.

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Section: Egr1 Is a Fibrotic Factormentioning

confidence: 99%

Section: Egr1 Is a Fibrotic Factormentioning

confidence: 99%

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Havis

Duprez

2020

IJMS

363

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“…TGF-βs are involved in all multicellular organisms and maintain tissue homeostasis through growth regulation, cell migration, differentiation, epithelial-mesenchymal transition, extracellular matrix remodeling, and immune reactions. However, aberrant overproduction of TGF-β ligands has been identi ed in diseases such as cancer, brosis, and in ammation where hyperactive TGF-β drives disease progression by modulating cell growth, migration, or various phenotypes [27][28][29]. Our results showed that TGF-β was aberrantly expressed following joint immobilization, promoting an in ammatory reaction.…”

Section: Discussionmentioning

confidence: 69%

Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats

Mao¹,

Mi²,

Pan³

et al. 2020

Preprint

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Background Joint contracture is a common complication of joint injury. This study aimed to assess the effect of inhibiting the transforming growth factor-β (TGF-β) signaling during joint immobilization and remobilization on immobilization-induced joint contracture in rats. Methods The knees of rats were immobilized using Kirschner wires following trauma to the femoral condyles to generate joint contracture. After immobilization, levels of TGF-β and passive extension range of motion (ROM) were measured at different time points, joints were histologically analyzed by hematoxylin and eosin (H&E) and Masson trichrome staining, and the expression of inflammatory or fibrosis-related mediators, including interleukin-1β (IL-1β), phosphorylated Smad2/3 (p-Smad2/3), α-smooth muscle actin (α-SMA) and collagen types I (Col 1) and III (Col 3), were examined in joint capsules using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Rats were also treated with LY2157299, a TGF-β receptor I kinase inhibitor, at different stages of immobilization and remobilization. Results TGF-β1 levels in the serum and the number of p-Smad2/3+ cells in the joint capsule were significantly elevated after immobilization. ROM decreased during the 6 weeks of immobilization and partly recovered after remobilization. After treatment with LY2157299 during immobilization, the restricted ROM moderately increased, but this effect was stronger when combined with active motion. Mechanistically, the expression of IL-1β, TGF-β, fibrosis-related factors, and the density of collagen significantly decreased after treatment with LY2157299. Conclusions Inhibiting TGF-β signaling paired with active motion effectively attenuated the formation of immobilization-induced joint contracture in rats.

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“…TGF-β and other inducers have been reported to trigger differentiation of dermal fibroblast to myofibroblast during scar formation [61,62]. TGF-β1-induced myofibroblast differentiation through the Smad2/3 signaling pathway increases Hsp47 expression levels [63].…”

Section: Resultsmentioning

confidence: 99%

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

Khan

Sankaran

Llontop

et al. 2020

BMC Mol and Cell Biol

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Background: Collagen is a structural protein that provides mechanical stability and defined architectures to skin. In collagen-based skin disorders this stability is lost, either due to mutations in collagens or in the chaperones involved in collagen assembly. This leads to chronic wounds, skin fragility, and blistering. Existing approaches to treat such conditions rely on administration of small molecules to simulate collagen production, like 4phenylbutyrate (4-PBA) or growth factors like TGF-β. However, these molecules are not specific for collagen synthesis, and result in unsolicited side effects. Hsp47 is a collagen-specific chaperone with a major role in collagen biosynthesis. Expression levels of Hsp47 correlate with collagen deposition. This article explores the stimulation of collagen deposition by exogenously supplied Hsp47 (collagen specific chaperone) to skin cells, including specific collagen subtypes quantification. Results: Here we quantify the collagen deposition level and the types of deposited collagens after Hsp47 stimulation in different in vitro cultures of cells from human skin tissue (fibroblasts NHDF, keratinocytes HaCat and endothelial cells HDMEC) and mouse fibroblasts (L929 and MEF). We find upregulated deposition of fibrillar collagen subtypes I, III and V after Hsp47 delivery. Network collagen IV deposition was enhanced in HaCat and HDMECs, while fibril-associated collagen XII was not affected by the increased intracellular Hsp47 levels. The deposition levels of fibrillar collagen were cell-dependent i.e. Hsp47-stimulated fibroblasts deposited significantly higher amount of fibrillar collagen than Hsp47-stimulated HaCat and HDMECs. Conclusions: A 3-fold enhancement of collagen deposition was observed in fibroblasts upon repeated dosage of Hsp47 within the first 6 days of culture. Our results provide fundamental understanding towards the idea of using Hsp47 as therapeutic protein to treat collagen disorders.

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TGF-β in fibrosis by acting as a conductor for contractile properties of myofibroblasts

Cited by 119 publications

References 161 publications

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

EGR1 Transcription Factor is a Multifaceted Regulator of Matrix Production in Tendons and Other Connective Tissues

Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats

Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro

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