Differential effects of transforming growth factor-β1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts

Matrix metalloproteinases (MMPs) are members of calcium dependent-zinc containing endopeptidases that play a pivotal role in extracellular matrix (ECM) remodeling. MMPs are also known to cleave non-matrix proteins, including cell surface receptors, TNF-α, angiotensin-II, growth factors, (especially transforming growth factor-β1, ΤGF- β1) plasminogen, endothelin and other bioactive molecules. The tissue inhibitors of metalloproteinases (TIMPs) inhibit the activity of MMPs and decrease ECM degradation. Various patho-physiological conditions have been linked with the imbalance of ECM synthesis and degradation. Numerous studies have reported the significance of MMPs and TIMPs in the progression of kidney pathologies, including glomerulonephritis, diabetic nephropathy, renal cancer, and nephrolithiasis. Although dysregulated activity of MMPs could directly or indirectly lead to pathological morbidities, their contribution in disease progression is still understated. Specifically, MMP activity in the kidneys and it's relation to kidney diseases has been the subject of a limited number of investigations. Therefore, the aim of the present review is to provide an updated insight of the involvement of MMPs and TIMPs in the pathogenesis of inflammatory and degenerative kidney disorders.

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JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

International Journal of Molecular Sciences ◽

10.3390/ijms22062952 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2952

Author(s):

Tzu-Yu Hou ◽

Shi-Bei Wu ◽

Hui-Chuan Kau ◽

Chieh-Chih Tsai

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Mapk Pathway ◽

Transforming Growth Factor Β1 ◽

Tissue Growth ◽

Mitogen Activated Protein Kinase ◽

Tissue Inhibitors Of Metalloproteinases ◽

Western Blots ◽

Orbital Fibroblasts ◽

Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

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Differential Effects of Transforming Growth Factor-β1 on Cellular Proliferation in the Developing Prostate

Endocrinology ◽

10.1210/en.2004-0526 ◽

2004 ◽

Vol 145 (9) ◽

pp. 4292-4300 ◽

Cited By ~ 26

Author(s):

Darren C. Tomlinson ◽

Sarah H. Freestone ◽

O. Cathal Grace ◽

Axel A. Thomson

Keyword(s):

Growth Factor ◽

Cellular Proliferation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Differential Effects

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YB-1 Coordinates Vascular Smooth Muscle α-Actin Gene Activation by Transforming Growth Factor β1 and Thrombin during Differentiation of Human Pulmonary Myofibroblasts

Molecular Biology of the Cell ◽

10.1091/mbc.e05-03-0216 ◽

2005 ◽

Vol 16 (10) ◽

pp. 4931-4940 ◽

Cited By ~ 40

Author(s):

Aiwen Zhang ◽

Xiaoying Liu ◽

John G. Cogan ◽

Matthew D. Fuerst ◽

John A. Polikandriotis ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Vascular Smooth Muscle ◽

Gene Transcription ◽

Transforming Growth Factor ◽

Human Fibroblasts ◽

Transforming Growth Factor Β1 ◽

Translational Efficiency ◽

Myofibroblast Differentiation ◽

Early Protein

Profibrotic regulatory mechanisms for tissue repair after traumatic injury have developed under strong evolutionary pressure to rapidly stanch blood loss and close open wounds. We have examined the roles played by two profibrotic mediators, transforming growth factor β1 (TGFβ1) and thrombin, in directing expression of the vascular smooth muscle α-actin (SMαA) gene, an important determinant of myofibroblast differentiation and early protein marker for stromal cell response to tissue injury. TGFβ1 is a well known transcriptional activator of the SMαA gene in myofibroblasts. In contrast, thrombin independently elevates SMαA expression in human pulmonary myofibroblasts at the posttranscriptional level. A common feature of SMαA up-regulation mediated by thrombin and TGFβ1 is the involvement of the cold shock domain protein YB-1, a potent repressor of SMαA gene transcription in human fibroblasts that also binds mRNA and regulates translational efficiency. YB-1 dissociates from SMαA enhancer DNA in the presence of TGFβ1 or its Smad 2, 3, and 4 coregulatory mediators. Thrombin does not effect SMαA gene transcription but rather displaces YB-1 from SMαA exon 3 coding sequences previously shown to be required for mRNA translational silencing. The release of YB-1 from promoter DNA coupled with its ability to bind RNA and shuttle between the nucleus and cytoplasm is suggestive of a regulatory loop for coordinating SMαA gene output in human pulmonary myofibroblasts at both the transcriptional and translational levels. This loop may help restrict organ-destructive remodeling due to excessive myofibroblast differentiation.

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