Mechanical compression upregulates MMP9 through SMAD3 but not SMAD2 modulation in hypertrophic scar fibroblasts

Huang, Dong; Liu, Yingping; Huang, Yating; Xie, Yuan; Shen, Kuan-Hong; Zhang, Dawei; Mou, Yong

doi:10.3109/03008207.2014.959118

Cited by 20 publications

(16 citation statements)

References 18 publications

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“…Pathological cutaneous wound healing resulting in excessive scarring and fibrosis is the consequence of an imbalance between ECM synthesis by myofibroblasts and degradation and remodeling by MMPs ( 13 ). We found that remodeling marker MMP-9 was increased after mechanical stress, which was also observed by other groups ( 58 – 60 ). VEGF is an important promoter of angiogenesis and therefore microvessel density might be increased by mechanical tension.…”

Section: Discussionsupporting

confidence: 89%

Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair

et al. 2015

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Mechanical stress following surgery or injury can promote pathological wound healing and fibrosis, and lead to functional loss and esthetic problems. Splinted excisional wounds can be used as a model for inducing mechanical stress. The cytoprotective enzyme heme oxygenase-1 (HO-1) is thought to orchestrate the defense against inflammatory and oxidative insults that drive fibrosis. Here, we investigated the activation of the HO-1 system in a splinted and non-splinted full-thickness excisional wound model using HO-1-luc transgenic mice. Effects of splinting on wound closure, HO-1 promoter activity, and markers of inflammation and fibrosis were assessed. After seven days, splinted wounds were more than three times larger than non-splinted wounds, demonstrating a delay in wound closure. HO-1 promoter activity rapidly decreased following removal of the (epi)dermis, but was induced in both splinted and non-splinted wounds during skin repair. Splinting induced more HO-1 gene expression in 7-day wounds; however, HO-1 protein expression remained lower in the epidermis, likely due to lower numbers of keratinocytes in the re-epithelialization tissue. Higher numbers of F4/80-positive macrophages, αSMA-positive myofibroblasts, and increased levels of the inflammatory genes IL-1β, TNF-α, and COX-2 were present in 7-day splinted wounds. Surprisingly, mRNA expression of newly formed collagen (type III) was lower in 7-day wounds after splinting, whereas, VEGF and MMP-9 were increased. In summary, these data demonstrate that splinting delays cutaneous wound closure and HO-1 protein induction. The pro-inflammatory environment following splinting may facilitate higher myofibroblast numbers and increase the risk of fibrosis and scar formation. Therefore, inducing HO-1 activity against mechanical stress-induced inflammation and fibrosis may be an interesting strategy to prevent negative effects of surgery on growth and function in patients with orofacial clefts or in patients with burns.

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Section: Discussionsupporting

confidence: 89%

Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair

et al. 2015

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“…Additionally, fibroblasts have been reported to degrade fibrin clots by generating MMPs and their inhibitors (TIMPs), leading to a disorder of matrix formation and degradation (49). The enhanced expression levels of MMP-2 and MMP-9 have been shown to be associated with decreased levels of collagen I and collagen III in HS tissues (50). In this study, we found that TGF-β1 significantly increased the MMP-2 and MMP-9 expression at the transcriptional and translational levels.…”

Section: Discussionmentioning

confidence: 99%

Botulinum toxin type A prevents the phenotypic transformation of fibroblasts induced by TGF‑β1 via the PTEN/PI3K/Akt signaling pathway

et al. 2019

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Hypertrophic scar (HS) is a common type of dermatosis. Botulinum toxin type A (BTXA) can exert an anti-HS effect; however, the regulatory mechanisms underlying this effect remain unclear. Thus, the aim of this study was to examine the effects of BTXA on phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and the fibroblast phenotypic transformation induced by transforming growth factor (TGF)-β1, which is an important regulatory factor involved in the process of HS. For this purpose, fibroblasts were treated with various concentrations of BTXA and then treated with 10 ng/ml of TGF-β1 with gradient concentrations of BTXA. The proliferation and apoptosis of fibroblasts were measured by cell counting kit-8 assay (CCK-8) and flow cytometry, respectively. PTEN methylation was analyzed by methylation-specific PCR (MSP) and DNA methyltransferase (DNMT) activity was determined using a corresponding kit. RT-qPCR and western blot analysis were performed to detect the transcription and translation levels. The results revealed that BTXA suppressed the proliferation and increased the apoptosis of fibroblasts treated with TGF-β1 in a dose-dependent manner. BTXA in combination with TGF-β1 suppressed the expression of molecules related to the extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and apoptosis. BTXA reduced the PTEN methylation level and downregulated the expression levels of methylation-associated genes. BTXA also inhibited the phosphorylation of phosphoinositide 3-kinase (PI3K) and Akt. On the whole, the findings of this study indicate that BTXA may inhibit fibroblast phenotypic transformation by regulating PTEN methylation and the phosphorylation of related pathways. The findings of this study can provide a theoretical basis for HS treatment.

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“…Mechanical strain is a known inducer of ECM remodeling in a number of tissues and organs, such as skin, 15 lung tissue, 11,16 bone, 17 and vascular systems. 18 Alterations include cell reorientation, matrix composition, collagen, and elastin realignment.…”

Section: Discussionmentioning

confidence: 99%

Mechanical Strain Induces Distinct Human Scleral Fibroblast Lineages: Differential Roles in Cell Proliferation, Apoptosis, Migration, and Differentiation

Qiu

Chen

Yao

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Mechanical compression upregulates MMP9 through SMAD3 but not SMAD2 modulation in hypertrophic scar fibroblasts

Abstract: These results demonstrate that compressive stress upregulates MMP9 by SMAD3 but not by SMAD2.

Cited by 20 publications

References 18 publications

Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair

Mechanical Stress Changes the Complex Interplay Between HO-1, Inflammation and Fibrosis, During Excisional Wound Repair

Botulinum toxin type A prevents the phenotypic transformation of fibroblasts induced by TGF‑β1 via the PTEN/PI3K/Akt signaling pathway

Mechanical Strain Induces Distinct Human Scleral Fibroblast Lineages: Differential Roles in Cell Proliferation, Apoptosis, Migration, and Differentiation

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