Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation

Klingberg, Franco; Chow, Melissa; Koehler, Anne; Boo, Stellar; Buscemi, Lara; Quinn, Thomas M.; Costell, Mercedes; Alman, Benjamin A.; Génot, Elisabeth; Hinz, Boris

doi:10.1083/jcb.201402006

Cited by 200 publications

(165 citation statements)

References 74 publications

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“…αvβ8 on lung fibroblasts has been suggested to take part in lung fibrosis, via a mechanism involving TGF-β activation by myofibroblasts [58]. Hinz has recently elegantly demonstrated that stiffness of the ECM can sensitize TGF-β to activation [59]. The importance of β1 integrin function for TGF-β signaling was also underlined by the phenotype of mice lacking the β1 integrin associated protein integrin-linked kinase (ILK) in fibroblasts [60].…”

Section: Tgf-β Activating Integrinsmentioning

confidence: 86%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

160

109

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Section: Tgf-β Activating Integrinsmentioning

confidence: 86%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

160

109

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“…It is regulated by a variety of mechanisms including ligand processing, phosphorylation, and inhibitory Smad proteins (Massague, 2012). ECM mechanical remodeling has been shown to regulate TGF‐β1 activation by releasing TGF‐β1 from the ECM microenvironment (Wells & Discher, 2008; Klingberg et al ., 2014). Our findings demonstrate another level of regulation of TGF‐β by mechanical force; reduced mechanical force can down‐regulate the ability of cells to respond to TGF‐β via specific down‐regulation of TβRII.…”

Section: Discussionmentioning

confidence: 99%

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

et al. 2015

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SummaryThe structural integrity of human skin is largely dependent on the quality of the dermal extracellular matrix (ECM), which is produced, organized, and maintained by dermal fibroblasts. Normally, fibroblasts attach to the ECM and thereby achieve stretched, elongated morphology. A prominent characteristic of dermal fibroblasts in aged skin is reduced size, with decreased elongation and a more rounded, collapsed morphology. Here, we show that reduced size of fibroblasts in mechanically unrestrained three‐dimensional collagen lattices coincides with reduced mechanical force, measured by atomic force microscopy. Reduced size/mechanical force specifically down‐regulates TGF‐β type II receptor (TβRII) and thus impairs TGF‐β/Smad signaling pathway. Both TβRII mRNA and protein were decreased, resulting in 90% loss of TGF‐β binding to fibroblasts. Down‐regulation of TβRII was associated with significantly decreased phosphorylation, DNA‐binding, and transcriptional activity of its key downstream effector Smad3 and reduced expression of Smad3‐regulated essential ECM components type I collagen, fibronectin, and connective tissue growth factor (CTGF/CCN2). Restoration of TβRII significantly increased TGF‐β induction of Smad3 phosphorylation and stimulated expression of ECM components. Reduced expression of TβRII and ECM components in response to reduced fibroblast size/mechanical force was fully reversed by restoring size/mechanical force. Reduced fibroblast size was associated with reduced expression of TβRII and diminished ECM production, in aged human skin. Taken together, these data reveal a novel mechanism that provides a molecular basis for loss of dermal ECM, with concomitant increased fragility, which is a prominent feature of human skin aging.

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“…Impaired VSMC differentiation in Mmp17 −/− mice could also be related to the altered ECM organization, which might directly decrease Tgfb1 availability. 33 Proteome analysis did not reveal changes in the levels of the contractile proteins smooth muscle myosin heavy chain or calponin but did indicate an important contribution to the phenotype from alterations to actomyosin and cell-adhesion pathways likely related to matrix/force-dependent responses. Proteomics analysis also identified mitochondrial dysfunction in the dedifferentiated phenotype of Mmp17-null aortic VSMCs, both in neonates and adults.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice

Martín-Alonso

García-Redondo

Guo

et al. 2015

Circulation Research

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A ortic aneurysm predisposes the aorta to dissection or rupture and causes 1% to 2% of deaths in developed countries.1 Thoracic aortic aneurysms and acute aortic dissections (TAADs) that affect young patients result primarily from genetic mutations. 2 The vulnerability of the aortic wall is mainly because of its poor ability to appropriately accommodate hemodynamic changes. The aortic wall, particularly in the thoracic aorta, is able to distend without requiring subsequent contraction of vascular smooth muscle cells (VSMCs) because of the elastic recoil provided by the layers of elastin lamellae.3 These mechanical properties depend on the intimate physical and mechanical connections of differentiated VSMCs with the extracellular matrix (ECM, mostly elastin, and collagen) that they produce and organize, connections that are established through force-dependent adhesion proteins (integrins), and the cytoskeleton (actin and myosin).3 During aortic development, VSMCs differentiate from neural crest and second heart field progenitors and also from mesenchymal progenitors recruited to the nascent endothelial tube; during this process, proper interaction needs to Molecular Medicine© 2015 American Heart Association, Inc. Rationale: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries.These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.Objective: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. be established between VSMCs and the ECM. 4 Detailed analysis of pulmonary artery development demonstrated that formation of the vessel wall involves the induction of successive layers of VSMCs and the invasion of the outer layers through the reorientation and radial migration of the inner ones. Methods and Results:5 Transforming growth factor (TGF)-B has been extensively studied as an inducer of VSMC maturation, and more recent studies have identified gradients of platelet-derived growth factor (PDGF)-B and other not-yet identified signals as regulators of VSMC differentiation, providing new insights into artery wall development. 5This intimate connection between VSMCs and the ECM ensures that alterations to one affect the other and can have similar effects on the overall mechanical behavior of the vessel. Thus, TAADs can be caused by mutations that affect VSMC function or that alter ECM composition and assembly.2 For example, Marfan syndrome, a genetic syndrome that predisposes to TAAD, is caused by mutations in the fibrillin-1 (FBN1) gene, which encodes an ECM protein necessary for proper elastin formation, 6 whereas in Loeys-Dietz syndrome, TGFB receptors type 1 and 2 (TGFBR1 and TGFBR2) are mutated, 7 resulting in impeded VSMC differentiation.8 Predispositi...

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Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation

Abstract: A mild strain induced by matrix remodeling mechanically primes latent TGF-β1 for its subsequent activation and release in response to contractile forces.

Cited by 200 publications

References 74 publications

Extracellular matrix component signaling in cancer

Extracellular matrix component signaling in cancer

Reduction of fibroblast size/mechanical force down‐regulates TGF ‐β type II receptor: implications for human skin aging

Deficiency of MMP17/MT4-MMP Proteolytic Activity Predisposes to Aortic Aneurysm in Mice

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