scholarly journals Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix

2007 ◽  
Vol 179 (6) ◽  
pp. 1311-1323 ◽  
Author(s):  
Pierre-Jean Wipff ◽  
Daniel B. Rifkin ◽  
Jean-Jacques Meister ◽  
Boris Hinz
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Mechanical Stress ◽  
Protease Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Stress Fibers ◽  
Fibrotic Diseases ◽  
Triton X ◽  
Tgf Β1

The conjunctive presence of mechanical stress and active transforming growth factor β1 (TGF-β1) is essential to convert fibroblasts into contractile myofibroblasts, which cause tissue contractures in fibrotic diseases. Using cultured myofibroblasts and conditions that permit tension modulation on the extracellular matrix (ECM), we establish that myofibroblast contraction functions as a mechanism to directly activate TGF-β1 from self-generated stores in the ECM. Contraction of myofibroblasts and myofibroblast cytoskeletons prepared with Triton X-100 releases active TGF-β1 from the ECM. This process is inhibited either by antagonizing integrins or reducing ECM compliance and is independent from protease activity. Stretching myofibroblast-derived ECM in the presence of mechanically apposing stress fibers immediately activates latent TGF-β1. In myofibroblast-populated wounds, activation of the downstream targets of TGF-β1 signaling Smad2/3 is higher in stressed compared to relaxed tissues despite similar levels of total TGF-β1 and its receptor. We propose activation of TGF-β1 via integrin-mediated myofibroblast contraction as a potential checkpoint in the progression of fibrosis, restricting autocrine generation of myofibroblasts to a stiffened ECM.

scholarly journals Effects of Transforming Growth Factor-β1 on Renal Extracellular Matrix Components and Their Regulating Proteins

1999 ◽  
Vol 10 (10) ◽  
pp. 2109-2119 ◽  
Author(s):  
JULIE A. DOUTHWAITE ◽  
TIMOTHY S. JOHNSON ◽  
JOHN L. HAYLOR ◽  
PHIL WATSON ◽  
A. MEGUID EL NAHAS
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Tissue Transglutaminase ◽  
Rat Kidney ◽  
Transforming Growth Factor Β1 ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Enzyme Linked Immunosorbent Assay ◽  
Extracellular Matrix Components ◽  
Tgf Β1

Abstract. Transforming growth factor-β1 (TGF-β1) is widely regarded as a potent fibrogenic renal growth factor. In cell culture, TGF-β1 has been shown to increase various extracellular matrix (ECM) proteins and tissue inhibitors of metalloproteinases (TIMP), while decreasing matrix metalloproteinases (MMP), providing the optimum environment for progressive ECM accumulation. This study, which uses the isolated perfused rat kidney (IPRK), describes for the first time in a whole kidney preparation the action of TGF-β1 on factors associated with ECM processing. This model allows the study of the intact rat kidney with physiologic cell-cell interactions in the absence of confounding systemic influences. Left kidneys were removed from male Wistar rats by a nonischemic technique and perfused with a sterile, apyrogenic, endotoxin-free perfusate, based on the plasma volume expander Hemaccel (polygeline), at constant pressure in a recirculating IPRK system. Kidneys were perfused for 1 h either with (n = 3) or without (n = 3) recombinant human TGF-β1 (20 ng/ml). The effects of perfusion were controlled by comparison with the nonperfused contralateral kidney (n = 6). TGF-β1 was measured in the perfusate and urine, at the start and end of the experiment using an enzyme-linked immunosorbent assay to its biologically active form. After perfusion, sections of the kidneys were analyzed for changes in mRNA by Northern blotting. Significant increases in mRNA for fibronectin (7.5-fold, P < 0.01), heparan sulfate proteoglycan core protein (53-fold, P < 0.001), laminin β1 (12-fold, P < 0.001), collagen α1(IV) (17-fold, P < 0.001), collagen α1(III) (fourfold, P < 0.001), and MMP9 (twofold, P < 0.05) were observed after perfusion with TGF-β1. Measurement of TIMP1, TIMP2, TIMP3, MMP1, and MMP2 mRNA demonstrated no detectable change, whereas determination of mRNA for tissue transglutaminase, an enzyme capable of cross-linking many ECM components, showed an eightfold increase (P < 0.01). This study suggests that in the IPRK and in the absence of other exogenous growth factors, TGF-β1 selectively increases the synthesis of ECM and tissue transglutaminase without changes that would result in the reduction of ECM degradation.

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

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.

scholarly journals Transforming growth factor-β1-induced N-cadherin drives cell–cell communication through connexin43 in osteoblast lineage

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yueyi Yang ◽  
Wenjing Liu ◽  
JieYa Wei ◽  
Yujia Cui ◽  
Demao Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gap Junction ◽  
Cell Line ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cx43 Expression ◽  
Mc3t3 Cell ◽  
Primary Osteoblasts ◽  
Tgf Β1 ◽  
Cell Cell

AbstractGap junction (GJ) has been indicated to have an intimate correlation with adhesion junction. However, the direct interaction between them partially remains elusive. In the current study, we aimed to elucidate the role of N-cadherin, one of the core components in adhesion junction, in mediating connexin 43, one of the functional constituents in gap junction, via transforming growth factor-β1(TGF-β1) induction in osteoblasts. We first elucidated the expressions of N-cadherin induced by TGF-β1 and also confirmed the upregulation of Cx43, and the enhancement of functional gap junctional intercellular communication (GJIC) triggered by TGF-β1 in both primary osteoblasts and MC3T3 cell line. Colocalization analysis and Co-IP experimentation showed that N-cadherin interacts with Cx43 at the site of cell–cell contact. Knockdown of N-cadherin by siRNA interference decreased the Cx43 expression and abolished the promoting effect of TGF-β1 on Cx43. Functional GJICs in living primary osteoblasts and MC3T3 cell line were also reduced. TGF-β1-induced increase in N-cadherin and Cx43 was via Smad3 activation, whereas knockdown of Smad3 signaling by using siRNA decreased the expressions of both N-cadherin and Cx43. Overall, these data indicate the direct interactions between N-cadherin and Cx43, and reveal the intervention of adhesion junction in functional gap junction in living osteoblasts.

Regulation of extracellular matrix synthesis by TNF-α and TGF-β1 in type II cells exposed to coal dust

1998 ◽  
Vol 275 (4) ◽  
pp. L637-L644 ◽  
Author(s):  
Yu-Chen Lee ◽  
D. Eugene Rannels
Keyword(s):  
Extracellular Matrix ◽  
Cell Cultures ◽  
Transforming Growth Factor ◽  
Coal Dust ◽  
Transforming Growth Factor Β1 ◽  
Type Ii ◽  
Tnf Α ◽  
Type Ii Cell ◽  
Primary Type ◽  
Tgf Β1

Type II pulmonary epithelial cells respond to anthracite coal dust PSOC 867 with increased synthesis of extracellular matrix (ECM) components. Alveolar macrophages modulate this response by pathways that may involve soluble mediators, including tumor necrosis factor-α (TNF-α) or transforming growth factor-β1 (TGF-β1). The effects of TNF-α (10 ng/ml) and/or TGF-β1 (2 ng/ml) were thus investigated in dust-exposed primary type II cell cultures. In control day 1 or day 3 cultures, TNF-α and/or TGF-β1 had little or no effect on the synthesis of type II cellular proteins, independent of whether the cells were exposed to dust. With PSOC 867 exposure, where ECM protein synthesis is elevated, TNF-α and TGF-β1 further increased both the absolute and relative rates of ECM synthesis on day 3 but had little effect on day 1. Each mediator increased expression of fibronectin mRNA, as well as of ECM fibronectin content, in a manner qualitatively similar to their effects on synthesis. Thus TNF-α and TGF-β1 modulate both ECM synthesis and fibronectin content in coal dust-exposed type II cell cultures.

scholarly journals Transforming Growth Factor β1 (TGF-β1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-α Signaling

2001 ◽  
Vol 21 (21) ◽  
pp. 7218-7230 ◽  
Author(s):  
Francesc Viñals ◽  
Jacques Pouysségur
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Cell Survival ◽  
Network Formation ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vitro Angiogenesis ◽  
Tgf Β1

ABSTRACT Mouse capillary endothelial cells (1G11 cell line) embedded in type I collagen gels undergo in vitro angiogenesis. Cells rapidly reorganize and form capillary-like structures when stimulated with serum. Transforming growth factor β1 (TGF-β1) alone can substitute for serum and induce cell survival and tubular network formation. This TGF-β1-mediated angiogenic activity depends on phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (MAPK) signaling. We showed that specific inhibitors of either pathway (wortmannin, LY-294002, and PD-98059) all suppressed TGF-β1-induced angiogenesis mainly by compromising cell survival. We established that TGF-β1 stimulated the expression of TGF-α mRNA and protein, the tyrosine phosphorylation of a 170-kDa membrane protein representing the epidermal growth factor (EGF) receptor, and the delayed activation of PI3K/Akt and p42/p44 MAPK. Moreover, we showed that all these TGF-β1-mediated signaling events, including tubular network formation, were suppressed by incubating TGF-β1-stimulated endothelial cells with a soluble form of an EGF receptor (ErbB-1) or tyrphostin AG1478, a specific blocker of EGF receptor tyrosine kinase. Finally, addition of TGF-α alone poorly stimulated angiogenesis; however, by reducing cell death, it strongly potentiated the action of TGF-β1. We therefore propose that TGF-β1 promotes angiogenesis at least in part via the autocrine secretion of TGF-α, a cell survival growth factor, activating PI3K/Akt and p42/p44 MAPK.

scholarly journals Transforming Growth Factor β1 (TGF-β1) Suppresses Growth of B-cell Lymphoma Cells by p14ARF-dependent Regulation of Mutant p53

2012 ◽  
Vol 287 (27) ◽  
pp. 23184-23195 ◽  
Author(s):  
Gang Chen ◽  
Paritosh Ghosh ◽  
Thomas O'Farrell ◽  
Rachel Munk ◽  
Louis J. Rezanka ◽  
...  
Keyword(s):  
Growth Factor ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Transforming Growth Factor Β1 ◽  
Mutant P53 ◽  
Lymphoma Cells ◽  
Tgf Β1
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