Smad3 is necessary for transforming growth factor-beta2 induced ocular hypertension in mice

McDowell, Colleen M; Tebow, Holly E.; Wordinger, Robert J.; Clark, Abbot F.

doi:10.1016/j.exer.2013.10.017

Cited by 61 publications

(84 citation statements)

References 27 publications

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“…Previously, we reported that TGFb2 induces ocular hypertension in mice. 4,16 Here, we confirm that Ad5.TGFb2 does indeed increase IOP with significant IOP differences at all time points measured post injection (days 3-18, P < 0.001; day 21, P < 0.05; Fig. 1A).…”

Section: Resultssupporting

confidence: 71%

“…We have previously reported that there is no difference in the gross morphology of the TM, gross morphology of the anterior chamber, or FN protein expression in the TM between Smad3 genotypes. 4 We have also previously reported that adenoviral injection can cause mild inflammation in the anterior chamber, but this inflammation does not affect ocular hypertension phenotypes based on the lack of ocular hypertension in animals injected with Ad5.null, Ad5.GFP, Ad5.MYOC WT , or Ad5hTGFb2 WT . 4,16,25,28 We recapitulate these data here by injecting Ad5.Gremlin into one eye of each Smad3 genotype.…”

Section: Resultsmentioning

confidence: 99%

“…4 Here, we used our in vivo mouse model system to test whether gremlin overexpression alters the ECM composition in the TM and elevates IOP via the Smad3-dependent signaling pathway. Homozygous WT, HET, and homozygous KO 129-Smad3 tm1Par /J mice were used in each of our experiments.…”

Section: Resultsmentioning

confidence: 99%

“…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 and alters the ECM in human TM cells.…”

mentioning

confidence: 99%

“…Primary open-angle glaucoma (POAG) is associated with changes in the ECM composition within the TM, increased AH outflow resistance, and elevated IOP. 1,2 Transforming growth factor-b2 signaling pathway has been shown to be an important regulator of ECM proteins in the TM, [3][4][5][6][7][8][9] and TGFb2 has been found to be elevated in the AH and TM of POAG patients. 7,[10][11][12][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.…”

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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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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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A global test for gene‐gene interactions based on random matrix theory

Frost

Amos

Moore

2016

Genetic Epidemiology

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Statistical interactions between markers of genetic variation, or gene‐gene interactions, are believed to play an important role in the etiology of many multifactorial diseases and other complex phenotypes. Unfortunately, detecting gene‐gene interactions is extremely challenging due to the large number of potential interactions and ambiguity regarding marker coding and interaction scale. For many data sets, there is insufficient statistical power to evaluate all candidate gene‐gene interactions. In these cases, a global test for gene‐gene interactions may be the best option. Global tests have much greater power relative to multiple individual interaction tests and can be used on subsets of the markers as an initial filter prior to testing for specific interactions. In this paper, we describe a novel global test for gene‐gene interactions, the global epistasis test (GET), that is based on results from random matrix theory. As we show via simulation studies based on previously proposed models for common diseases including rheumatoid arthritis, type 2 diabetes, and breast cancer, our proposed GET method has superior performance characteristics relative to existing global gene‐gene interaction tests. A glaucoma GWAS data set is used to demonstrate the practical utility of the GET method.

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