In vivo interactions of TGF-β and extracellular matrix

doi:10.1016/0955-2235(92)90017-C

Progress in Growth Factor Research

Volume 4, Issue 4, 1992, Pages 369-382

Progress in Growth F...

https://doi.org/10.1016/0955-2235(92)90017-C Get rights and content

Abstract

TGF-β, a multifunctional cytokine, plays an important role in embryogenesis and in regulating repair and remodeling following tissue injury. Many of the biological actions of TGF-β are mediated by widespread effects on deposition of extracellular matrix. TGF-β stimulates the synthesis of individual matrix components including proteoglycans, collagens and glycoproteins. TGF-β also blocks matrix degradation by decreasing the synthesis of proteases and increasing the synthesis of protease inhibitors. Finally, TGF-β increases the synthesis of matrix receptors and alters their relative proportions on the surface of cells in a manner that could facilitate adhesion to matrix. All of these events have largely been demonstrated in vitro in cultured cells. In an experimental model of glomerulonephritis we have shown that TGF-β is responsible for the accumulation of pathological matrix in the glomeruli following immunological injury. Furthermore, all three of TGF-β's actions on extracellular matrix—increased synthesis, decreased degradation and modulation of receptors—have now been documented to be involved in matrix deposition in vivo in this model. Administration of the proteoglycan decorin suppressed TGF-β-induced matrix deposition in the nephritic glomeruli, thus confirming a physiological role for decorin as a regulator of TGF-β. Inhibitors of TGF-β may be important future drugs in treating fibrotic diseases caused by overproduction of TGF-β.

References (38)

E Balza et al.
Transforming growth factor β regulates the levels of different fibronectin isoforms in normal human cultured fibroblasts
FEBS Lett.
(1988)
A Bassols et al.
Transforming growth factor β regulates the expression and structure of extracellular matrix chondroitin/dermatan sulfate proteoglycans
J Biol Chem
(1988)
WA Border et al.
Transforming growth factor-β regulates production of proteoglycans by mesangial cells
Kidney Int.
(1990)
RA Ignotz et al.
Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix
J Biol Chem.
(1986)
RA Ignotz et al.
Cell adhesion protein receptors as targets for transforming growth factor-β action
Cell
(1987)
CL Jones et al.
Pathogenesis of interstitial fibrosis in chronic purine aminonucleoside nephrosis
Kidney Int.
(1991)
S-J Kim et al.
Promoter sequences of the human transforming growth factor-β1 gene responsive to transforming growth factor-β1 autoinduction
J Biol Chem.
(1989)
M Laiho et al.
Transforming growth factor-β induction of type-1 plasminogen activator inhibitor
J Biol Chem.
(1987)
CM Overall et al.
Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-β
J Biol Chem.
(1989)
M Shah et al.
Control of scarring in adult wounds by neutralizing antibody to transforming growth factor β
Lancet
(1992)

S Tomooka et al.

Glomular matrix accumulation is linked to inhibition of the plasmin protease system

Kidney Int.

(1992)

A Wang et al.

Polarized regulation of fibronectin secretion and alternative splicing by transforming growth factor β

J Biol Chem.

(1991)

R. Assoain et al.

Type β transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells

J Cell Biol.

(1986)

WA Border et al.

Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease

Nature

(1992)

WA Border et al.

Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1

Nature

(1990)

WA Border et al.

Extracellular matrix and glomerular disease

Sem Nephrol.

(1989)

WA Border et al.

Transforming growth factor-β: The dark side of tissue repair

J Clin Invest.

(1992)

DR Edwards et al.

Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor

EMBO J.

(1987)

LI Gold et al.

TGF-β selectively induces neutrophil chemotaxis

J Cell Biochem Suppl.

(1990)

Cited by (79)

Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease
2022, JHEP Reports
Citation Excerpt :
However, intrinsic expression of decorin along with TGF-β1 in liver tissue of 43 patients with chronic hepatitis and cirrhosis did not prevent liver fibrosis progression.80 Overall, decorin is a highly specific natural inhibitor of TGF-β.81 As mentioned, TGF-β is present in a latent complex in the ECM until a specific signal triggers its release.82
Transforming growth factor-β (TGF-β) is a potent effector in the liver, which is involved in a plethora of processes initiated upon liver injury. TGF-β affects parenchymal, non-parenchymal, and inflammatory cells in a highly context-dependent manner. Its bioavailability is critical for a fast response to various insults. In the liver – and probably in other organs – this is made possible by the deposition of a large portion of TGF-β in the extracellular matrix as an inactivated precursor form termed latent TGF-β (L-TGF-β). Several matrisomal proteins participate in matrix deposition, latent complex stabilisation, and activation of L-TGF-β. Extracellular matrix protein 1 (ECM1) was recently identified as a critical factor in maintaining the latency of deposited L-TGF-β in the healthy liver. Indeed, its depletion causes spontaneous TGF-β signalling activation with deleterious effects on liver architecture and function. This review article presents the current knowledge on intracellular L-TGF-β complex formation, secretion, matrix deposition, and activation and describes the proteins and processes involved. Further, we emphasise the therapeutic potential of toning down L-TGF-β activation in liver fibrosis and liver cancer.
Anionic biopolyelectrolytes of the syndecan/perlecan superfamily: Physicochemical properties and medical significance
2014, Advances in Colloid and Interface Science
In the review article presented here, we demonstrate that the connective tissue is more than just a matrix for cells and a passive scaffold to provide physical support. The extracellular matrix can be subdivided into proteins (collagen, elastin), glycoconjugates (structural glycoproteins, proteoglycans) and glycosaminoglycans (hyaluronan). Our main focus rests on the anionic biopolyelectrolytes of the perlecan/syndecan superfamily which belongs to extracellular matrix and cell membrane integral proteoglycans. Though the extracellular domain of the syndecans may well be performing a structural role within the extracellular matrix, a key function of this class of membrane intercalated proteoglycans may be to act as signal transducers across the plasma membrane and thus be more appropriately included in the group of cell surface receptors. Nevertheless, there is a continuum in functions of syndecans and perlecans, especially with respect to their structural role and biomedical significance.
HS/CS proteoglycans are receptor sites for lipoprotein binding thus intervening directly in lipid metabolism. We could show that among all lipoproteins, HDL has the highest affinity to these proteoglycans and thus instals a feedforward forechecking loop against atherogenic apoB100 lipoprotein deposition on surface membranes and in subendothelial spaces. Therefore, HDL is not only responsible for VLDL/IDL/LDL cholesterol exit but also controls thoroughly the entry. This way, it inhibits arteriosclerotic nanoplaque formation. The ternary complex ‘lipoprotein receptor (HS/CS-PG) – lipoprotein (LDL, oxLDL, Lp(a)) – calcium’ may be interpreted as arteriosclerotic nanoplaque build-up on the molecular level before any cellular reactivity, possibly representing the arteriosclerotic primary lesion combined with endothelial dysfunction. With laser-based ellipsometry we could demonstrate that nanoplaque formation is a Ca²⁺-driven process. In an in vitro biosensor application of HS-PG coated silica surfaces we tested nanoplaque formation and size in clinical trials with cardiovascular high-risk patients who underwent treatment with ginkgo or fluvastatin. While ginkgo reduced nanoplaque formation (size) by 14.3% (23.4%) in the isolated apoB100 lipid fraction at a normal blood Ca²⁺ concentration, the effect of the statin with a reduction of 44.1% (25.4%) was more pronounced. In addition, ginkgo showed beneficial effects on several biomarkers of oxidative stress and inflammation.
Besides acting as peripheral lipoprotein binding receptor, HS/CS-PG is crucially implicated in blood flow sensing. A sensor molecule has to fulfil certain mechanochemical and mechanoelectrical requirements. It should possess viscoelastic and cation binding properties capable of undergoing conformational changes caused both mechanically and electrostatically. Moreover, the latter should be ion-specific. Under no-flow conditions, the viscoelastic polyelectrolyte at the endothelium — blood interface assumes a random coil form. Blood flow causes a conformational change from the random coil state to the directed filament structure state. This conformational transition effects a protein unfurling and molecular elongation of the GAG side chains like in a ‘stretched’ spring. This configuration is therefore combined with an increase in binding sites for Na⁺ ions. Counterion migration of Na⁺ along the polysaccharide chain is followed by transmembrane Na⁺ influx into the endothelial cell and by endothelial cell membrane depolarization. The simultaneous Ca²⁺ influx releases NO and PGI₂, vasodilatation is the consequence. Decrease in flow reverses the process. Binding of Ca²⁺ and/or apoB100 lipoproteins (nanoplaque formation) impairs the flow sensor function.
The physicochemical and functional properties of proteoglycans are due to their amphiphilicity and anionic polyelectrolyte character. Thus, they potently interact with cations, albeit in a rather complex manner. Utilizing ²³Na⁺ and ³⁹ K⁺ NMR techniques, we could show that, both in HS-PG solutions and in native vascular connective tissue, the mode of interaction for monovalent cations is competition. Mg²⁺ and Ca²⁺ ions, however, induced a conformational change leading to an increased allosteric, cooperative K⁺ and Na⁺ binding, respectively. Since extracellular matrices and basement membranes form a tight-fitting sheath around the cell membrane of muscle and Schwann cells, in particular around sinus node cells of the heart, and underlie all epithelial and endothelial cell sheets and tubes, a release of cations from or an adsorption to these polyanionic macromolecules can transiently lead to fast and drastic activity changes in these tiny extracellular tissue compartments. The ionic currents underlying pacemaker and action potential of sinus node cells are fundamentally modulated. Therefore, these polyelectrolytic ion binding characteristics directly contribute to and intervene into heart rhythm.
Cell-ECM Interactions in Repair and Regeneration
2013, Handbook of Stem Cells
Cell–ECM Interactions in Repair and Regeneration
2012, Handbook of Stem Cells, Second Edition: Volume 1-2
Astragaloside IV attenuates myocardial fibrosis by inhibiting TGF-β1 signaling in coxsackievirus B3-induced cardiomyopathy
2011, European Journal of Pharmacology
Citation Excerpt :
TGF-β1 strongly contributes to fibrotic disorders of myocarditis (Pohlers et al., 2009). TGF-β1Inhibitors may be important future drugs for the treatment of fibrotic diseases caused by over-production of TGF-β1 (Noble et al., 1992). The antifibrotic mechanism of astragaloside IV in liver fibrogenesis may also be associated with TGF-β1downregulation, which results in fibrosis suppression (Liu et al., 2009a).
Myocardial fibrosis plays an important role in coxsackievirus B3 (CVB3) induced dilated cardiomyopathy. Excessive transforming growth factor (TGF)-β1 contributes to a pathologic excess of tissue fibrosis. We investigated the effect of astragaloside IV on myocardial fibrosis in CVB3-induced dilated cardiomyopathy. BALB/c mice were inoculated with CVB3 to induce acute viral myocarditis on day 7 (acute VMC group), monthly for 3 months to induce chronic myocarditis (chronic VMC group), and monthly for 9 months to induce dilated cardiomyopathy (DCM group). The same method was used for the DCM+Astra group as that of the DCM group, but former group was given with astragaloside IV-containing drinking water. Compared to DCM group, astragaloside IV treatment significantly increased the survival rate. Histological findings and the collagen volume fraction showed that astragaloside IV decreased fibrosis in heart tissues. Astragaloside IV decreased the level of the serum carboxy-terminal propeptide of procollagen type I (PICP) and the ratio of PICP/ N-terminal type I procollagen propeptide (PINP). Ameliorated myocardial fibrosis was consistent with the downregulated expression of TGF-β1 and its downstream pSmad2/3 and Smad4 in the myocardium of the DCM+Astra group compared to the DCM group. The level of type I collagen was lower in the DCM+Astra group than the DCM group. The same effect was found in the in vitro study. These findings showed that astragaloside IV had a potent preventive effect on myocardial fibrosis in CVB3-induced dilated cardiomyopathy that might be due to downregulation of TGF-β1-Smad signaling.
Cell-ECM Interactions in Repair and Regeneration
2011, Principles of Regenerative Medicine, Second Edition
This chapter discusses the composition and diversity of some of the better-known extracellular matrix (ECM) molecules and their receptors and explains selected examples illustrating the dynamics of cell–ECM interactions during wound healing and regeneration and the potential mechanisms involved in the signal transduction pathways initiated by these interactions. The ECM is a molecular complex that consists of collagens and other glycoproteins, hyaluronan, proteoglycans, glycosaminoglycans, and elastins and this complex interacts with molecules such as growth factors, cytokines, and matrix-degrading enzymes and their inhibitors. Growth factors and cytokines interact with the ECM in a variety of ways that allow them to affect each other. The ECM can influence the local concentration and biological activity of growth factors and cytokines by serving as a reservoir that binds them and protects them from being degraded, by presenting them more efficiently to their receptors, or by affecting their synthesis. A feature of ECM/growth factor interactions that is recently characterized involves the ability of specific domains of various ECM molecules, including laminin-5, tenascin-C, and decorin, to bind and activate growth factor receptors. The ability of ECM molecules to serve as ligands for growth factor receptors may facilitate a stable signaling environment for the associated cells due to the inability of the ligand to either diffuse or be internalized, thus serving as a long-term promigratory and/or proproliferative signal. The interactions between ECM molecules and their receptors can transmit signals directly or indirectly to signaling molecules within the cell, leading to a cascade of events and the coordinated expression of a variety of genes involved in cell adhesion, migration, proliferation, differentiation, and death.

View all citing articles on Scopus

View full text

In vivo interactions of TGF-β and extracellular matrix

Abstract

FEBS Lett.

J Biol Chem

Kidney Int.

J Biol Chem.

Cell

Kidney Int.

J Biol Chem.

J Biol Chem.

J Biol Chem.

Lancet

Kidney Int.

J Biol Chem.

Type β transforming growth factor in human platelets: release during platelet degranulation and action on vascular smooth muscle cells

J Cell Biol.

Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease

Nature

Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1

Nature

Extracellular matrix and glomerular disease

Sem Nephrol.

Transforming growth factor-β: The dark side of tissue repair

J Clin Invest.

Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor

EMBO J.

TGF-β selectively induces neutrophil chemotaxis

J Cell Biochem Suppl.