Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Akhmetshina, Alfiya; Dees, Clara; Pileckytė, Margarita; Szűcs, Gabriella; Spriewald, Bernd; Zwerina, Jochen; Distler, Oliver; Schett, Georg; Distler, Jörg H W

doi:10.1002/art.23677

Cited by 109 publications

(90 citation statements)

References 40 publications

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“…Rho GTPase activation is known to induce ␣-SMA expression and assembly in other cell types as well (30,55). As in the case of TM cells (63), the Rho/Rho kinase pathway has been shown to induce ECM synthesis in other mechanosensing cell types, including vascular endothelial cells and fibroblasts (2,6,43). In addition, mechanical stress, shear stress, and ECM stiffness have been recognized to influence Rho GTPase activity in different cell types, indicating an existence of a potential feedforward and feedback interplay between Rho-regulated myosin II contractile tension and ECM-derived mechanical force/rigidity (3,4,20,23,46,52).…”

Section: Discussionmentioning

confidence: 99%

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

177

222

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Pattabiraman PP, Rao PV. Mechanistic basis of Rho GTPaseinduced extracellular matrix synthesis in trabecular meshwork cells. Am J Physiol Cell Physiol 298: C749 -C763, 2010. First published November 25, 2009 doi:10.1152/ajpcell.00317.2009.-Elevated intraocular pressure arising from impaired aqueous humor drainage through the trabecular pathway is a major risk factor for glaucoma. To understand the molecular basis for Rho GTPase-mediated resistance to aqueous humor drainage, we investigated the possible interrelationship between actomyosin contractile properties and extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells expressing a constitutively active form of RhoA (RhoAV14). TM cells expressing RhoAV14 exhibited significant increases in fibronectin, tenascin C, laminin, ␣-smooth muscle actin (␣-SMA) levels, and matrix assembly in association with increased actin stress fibers and myosin light-chain phosphorylation. RhoAV14-induced changes in ECM synthesis and actin cytoskeletal reorganization were mimicked by lysophosphatidic acid and TGF-␤2, known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-␤ 2 stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and ␣-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and ␣-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-␤ 2-stimulated) via the use of short hairpin RNA decreased ␣-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced ␣-SMA expression in an SRF-dependent manner. Collectively, data on RhoA-induced changes in actomyosin contractile activity, ECM synthesis/assembly, and Erk activation, along with fibronectin-induced ␣-SMA expression in TM cells, reveal a potential molecular interplay between actomyosin cytoskeletal tension and ECM synthesis/assembly. This interaction could be significant for the homeostasis of aqueous humor drainage through the pressure-sensitive trabecular pathway. fibronectin; actomyosin; extracellular signal-regulated kinases; serum response factor GLAUCOMA IS A SECOND MAJOR cause of blindness in the United States. A major risk factor for primary open-angle glaucoma is elevated intraocular pressure caused by increased resistance to aqueous humor outflow localized within the trabecular pathway (15,56). Abnormal accumulation of extracellular matrix (ECM) and/or extracellular material, which increases resistance to drainage of aqueous humor through the trabecular pathway, is believed to be partly responsible for the elevated intraocular pressure and primary open-angle glaucoma (24,28,49). The cellular mechanisms that regulate the production and turnover of ECM within the outflow pathway and how ECM turnover is linked to regulation of aqueous humor outflow through the trabecular meshwork (TM) are far from clearly understood (13,...

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Section: Discussionmentioning

confidence: 99%

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Pattabiraman¹,

Rao

2010

American Journal of Physiology-Cell Physiology

177

222

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“…Finally, ROCK activity has also been implicated in dermal fibrosis, in ex vivo experiments with fibroblasts isolated from the affected skin of persons with scleroderma. ROCK inhibition of these fibroblasts prevented TGF-b-induced myofibroblast differentiation and extracellular matrix production (Akhmetshina et al, 2008). The antifibrotic effects of ROCK genetic Rho Kinases in Pulmonary Fibrosis targeting or pharmacologic inhibition in so many different models suggests that ROCK activation is centrally involved in the development of fibrosis in most organs.…”

Section: Involvement Of Rho-associated Coiled-coil Forming Proteimentioning

confidence: 99%

The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

Knipe¹,

Tager²,

Liao³

2014

Pharmacol Rev

185

143

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“…Human fibroblasts were prepared as outgrowth cultures from 5 healthy oral mucosa biopsies, and were subsequently cultured as previously described (14). In selected experiments, fibroblasts were stimulated with recombinant TGF-β (10 ng/ml; R&D Systems, Ambington, UK) and 5, 10 and 15 µM chloroquine (CQ; C6628; Sigma-Aldrich, St. Louis, MO, USA), an autophagy inhibitor.…”

Section: Autophagy Mediates Oral Submucous Fibrosismentioning

confidence: 99%

Autophagy mediates oral submucous fibrosis

Jiang

Zhao

Zhang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Oral submucous fibrosis (OSF) is a chronic insidious disease of the oral mucosa, well-recognized as a premalignant condition and commonly found in Southern China. It is primarily caused by the habit of areca nut or gutkha chewing. OSF is believed to be a homeostatic disorder of the extracellular matrix and fibroblast proliferation. The present study demonstrated a novel link between autophagy and OSF. Tissue samples from human OSF showed an overexpression of the autophagy marker microtubule-associated protein 1 light chain 3 using immunohistochemistry and quantitative polymerase chain reaction. With regard to the crucial role of transforming growth factor (TGF)-β in OSF disease, western blot analysis demonstrated that TGF-β signaling was shown to contribute to the activation of autophagy in fibroblasts in vitro; however, a cell apoptosis and MTS assay demonstrated that the suppression of autophagy ameliorated the fibrosis induced by active TGF-β receptor type I signaling, as well as promoted fibroblast apoptosis and suppressed proliferation. Therefore, the present results suggest that autophagy serves a crucial function in OSF.

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Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Cited by 109 publications

References 40 publications

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells

The Rho Kinases: Critical Mediators of Multiple Profibrotic Processes and Rational Targets for New Therapies for Pulmonary Fibrosis

Autophagy mediates oral submucous fibrosis

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