Role of TGFβ/Smad Signaling in Gremlin Induction of Human Trabecular Meshwork Extracellular Matrix Proteins

Sethi, Anirudh; Jain, Ankur; Zode, Gulab; Wordinger, Robert J.; Clark, Abbot F.

doi:10.1167/iovs.11-7587

Cited by 87 publications

(96 citation statements)

References 45 publications

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“…Transforming growth factor-1 (TGF 1) is the most potent cytokine that can promote the activation of HSCs, and gremlin is a downstream molecule of TGF-. There is evidence showing that TGF-1 can specifically increase the protein and mRNA expression of gremlin, which has been found to be related to the fibrosis (Sethi et al, 2011). Thus, to block the above targets to inhibit the fibrosis is of great importance in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Effects of neferine on TGF-β1 induced proliferation and gremlin expression in hepatic stellate cells

Li¹,

Lou²,

Wu³

et al. 2012

Bangladesh J Pharmacol

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To clarify the possible molecular mechanism underlying the anti-fibrotic effect of neferine (Nef), we investigated the in vitro effects of Nef on the proliferation of hepatic stellate cells and expressions of gremlin, TGF-1 and -SMA in these cells. TGF-1 had no influence on the proliferation of HSC-T6 cells (p>0.05) but significantly up-regulated the mRNA and protein expressions of gremlin, TGF-1 and -SMA in these cells (p<0.005). Nef could inhibit the proliferation of HSC-T6 cells in a dose and time dependent manner, and down -regulate the mRNA and protein expression of gremlin, TGF-1 and -SMA in these cells (p<0.005). Nef is an effective drug that can inhibit the proliferation of hepatic stellate cells to improve the hepatic fibrosis. Gremlin involves in the occurrence and development of hepatic fibrosis and may become a promising target in the treatment of hepatic fibrosis.

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Section: Introductionmentioning

confidence: 99%

Effects of neferine on TGF-β1 induced proliferation and gremlin expression in hepatic stellate cells

Li¹,

Lou²,

Wu³

et al. 2012

Bangladesh J Pharmacol

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“…Gremlin also elevates IOP in perfusion-cultured human anterior segments. 5,9 Here, we demonstrate that gremlin induces ocular hypertension and alters the ECM composition in the TM of mice. We also show that gremlin signaling through the canonical Smad pathway is essential for this gremlin-induced ocular hypertension.…”

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confidence: 66%

“…9 We have also shown that gremlin alone can induce these ECM proteins in TM cells. 5 The TM is a key tissue in IOP regulation. Therefore, we determined the effect of gremlin overexpression on IOP in mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Gremlin Induces Ocular Hypertension in Mice Through Smad3-Dependent Signaling

McDowell

Hernandez

Mao

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Transforming growth factor-b2 induces extracellular matrix (ECM) remodeling, which likely contributes to the defective function of the trabecular meshwork (TM) leading to glaucomatous ocular hypertension. Bone morphogenetic proteins (BMPs) inhibit these profibrotic effects of TGFb2. The BMP antagonist gremlin is elevated in glaucomatous TM cells and increases IOP in an ex vivo perfusion culture model. The purpose of this study was to determine whether gremlin regulates ECM proteins in the TM, signals through the Smad3-dependent pathway, and induces ocular hypertension in mice.METHODS. Ad5.Gremlin or Ad5.TGFb2 was injected intravitreally into one eye of each mouse. Intraocular pressure measurements were taken using a TonoLab tonometer. Gremlin, TGFb2, fibronectin (FN), and collagen-1 (Col-1) expression in the TM was determined by immunofluorescence, Western immunoblot, and quantitative (q)PCR analyses.RESULTS. Ad5.Gremlin or Ad5.TGFb2 each caused significant IOP elevation in mice.Immunofluorescence and Western blot analysis demonstrated that gremlin and TGFb2 reciprocally increased the expression of each other, and both increased FN expression in the TM and surrounding tissues. Ad5.Gremlin elevated IOP and increased Fn and Col-1 gene expression in the TM of Smad3 wild-type (WT) mice, but had no effect in Smad3 HET or Smad3 KO mice.CONCLUSIONS. Our results demonstrate that intravitreal injections of either Ad5.Gremlin or Ad5.TGFb2 elevate IOP and upregulate the ECM protein FN in the TM of mice. These data show that gremlin signals through the Smad3-dependent pathway in the TM to elevate IOP. We determined for the first time gremlin's role in inducing ocular hypertension in an in vivo model system. Keywords: gremlin, glaucoma, trabecular meshwork, TGFb2, intraocular pressure E levated IOP is a well-known causative risk factor for both the development and progression of glaucoma. Intraocular pressure is regulated by aqueous humor (AH) production in the ciliary body and drainage from the eye via the trabecular meshwork (TM) and uveoscleral pathway. The role of the TM and the surrounding extracellular matrix (ECM) in IOP regulation has been extensively studied. Primary open-angle glaucoma (POAG) is associated with changes in the ECM composition within the TM, increased AH outflow resistance, and elevated IOP. 1,2Transforming growth factor-b2 signaling pathway has been shown to be an important regulator of ECM proteins in the TM, 3-9 and TGFb2 has been found to be elevated in the AH and TM of POAG patients. 7,10-13 Transforming growth factor-b2 has also been shown to cause ocular hypertension in both ex vivo anterior segment perfusion organ culture models, 14,15 and by overexpression of a bioactivated form of TGFb2 in mouse eyes. 4,16 Transforming growth factor-b2 is known to regulate the expression of ECM proteins through the canonical Smad pathway as well as noncanonical signaling pathways. [17][18][19][20] We have previously demonstrated that TGFb2 signals through the canonical Smad and non-Smad pathways an...

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“…[23][24][25][26][27][28] A great deal of effort has gone into exploring how these different bioactive agents influence TM tissue properties and cell biology in the context of AH outflow in both in vitro and in vivo studies. 15,16,24,[29][30][31][32][33][34][35][36] These efforts are beginning to unravel the participation of several different intracellular signaling mechanisms, including Rho GTPase, Wnt, ECM/ mechanotransduction, integrins, nitric oxide, PKC, BMPs/ SMADs, MAP kinases, and others, in regulating contractile properties of TM cells, ECM turnover, adhesive interactions, biomechanical properties, permeability, and survival of outflow pathway tissues and cells. 14,24,[37][38][39][40] These different observations offer significant insights into the regulation of AH outflow and suggest several novel avenues to target selected signaling pathways and other molecular targets for increasing AH outflow through the conventional pathway, and for the development of new and mechanism-based IOP lowering drugs.…”

Section: Introductionmentioning

confidence: 99%

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Rao

2014

Journal of Ocular Pharmacology and Therapeutics

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Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

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Role of TGFβ/Smad Signaling in Gremlin Induction of Human Trabecular Meshwork Extracellular Matrix Proteins

Abstract: Gremlin employs canonical TGFβ2/Smad signaling to induce ECM genes and proteins in cultured human TM cells. Gremlin also induces both TGFβ2 and CTGF, which can act downstream to mediate some of these ECM changes in TM cells.

Cited by 87 publications

References 45 publications

Effects of neferine on TGF-β1 induced proliferation and gremlin expression in hepatic stellate cells

Effects of neferine on TGF-β1 induced proliferation and gremlin expression in hepatic stellate cells

Gremlin Induces Ocular Hypertension in Mice Through Smad3-Dependent Signaling

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

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