Effects of TGF-β2, BMP-4, and Gremlin in the Trabecular Meshwork: Implications for Glaucoma

Wordinger, Robert J.; Fleenor, Debra L.; Hellberg, Peggy E.; Pang, Iok Hou; Tovar, T.; Zode, Gulab; Fuller, John A.; Clark, Abbot F.

doi:10.1167/iovs.06-0296

Cited by 208 publications

(208 citation statements)

References 37 publications

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“…(Liton et al 2006) The fibronectin change and perhaps other aspects of this study could be related to TGFβ2, BMP-4 and Gremlin studies recently reported. (Wordinger et al 2007) In other studies of glaucomatous outflow tissue, calcification markers relating to matrix Gla protein and BMP-2 action appear to be modified, although mechanisms remain to be established. (Xue et al 2006;Xue et al 2007) Increases in soluble CD44, particularly the phosphorylated form, have also been recently linked to glaucoma, although causal relationships remain to be established.…”

Section: Glaucoma and Ecmmentioning

confidence: 98%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

424

443

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The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

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Section: Glaucoma and Ecmmentioning

confidence: 98%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

424

443

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“…We recently discovered that the biological effects of TGF-β in the TM can be modulated by the bone morphogenic proteins (BMPs) and their antagonist gremlin (46). These findings highlight the intricate interrelationships among signaling pathways, because BMP and Wnt signals can interact to coordinate tissue development.…”

Section: Figurementioning

confidence: 99%

Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure

et al. 2008

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Elevated intraocular pressure (IOP) is the principal risk factor for glaucoma and results from excessive impedance of the fluid outflow from the eye. This abnormality likely originates from outflow pathway tissues such as the trabecular meshwork (TM), but the associated molecular etiology is poorly understood. We discovered what we believe to be a novel role for secreted frizzled-related protein-1 (sFRP-1), an antagonist of Wnt signaling, in regulating IOP. sFRP1 was overexpressed in human glaucomatous TM cells. Genes involved in the Wnt signaling pathway were expressed in cultured TM cells and human TM tissues. Addition of recombinant sFRP-1 to ex vivo perfusion-cultured human eyes decreased outflow facility, concomitant with reduced levels of β-catenin, the Wnt signaling mediator, in the TM. Intravitreal injection of an adenoviral vector encoding sFRP1 in mice produced a titer-dependent increase in IOP. Five days after vector injection, IOP increased 2 fold, which was significantly reduced by topical ocular administration of an inhibitor of a downstream suppressor of Wnt signaling. Thus, these data indicate that increased expression of sFRP1 in the TM appears to be responsible for elevated IOP in glaucoma and restoring Wnt signaling in the TM may be a novel disease intervention strategy for treating glaucoma.

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“…The canonical BMP pathway and activin and TGFb pathway antagonize one another in numerous physiological contexts, including in early embryonic development, where SMAD2 antagonizes SMAD1 to establish body patterning (Yamamoto et al, 2009), in angiogenesis, where the balance of SMAD1/5/8 and SMAD2/3 establishes an angiogenic switch between activation and resolution phases (Goumans et al, 2003), in cell fate of type 2 alveolar epithelial cells, where trans-differentiation to a type 1 alveolar program is promoted by SMAD2/3, but restricted by SMAD1/5/8 , during maintenance of epithelial cell polarity, where SMAD1/5/8 restricts the TGFbinduced epithelial-mesenchymal transition (Saitoh et al, 2013), and during regulation of skeletal muscle mass, where SMAD1/5/8 and SMAD2/3 signaling inversely impact on muscle hypertrophy (Sartori et al, 2013;Winbanks et al, 2013). Moreover, imbalances in the ratio of TGFb superfamily cytokines are increasingly associated with human diseases, including pulmonary and kidney fibrosis (Izumi et al, 2006;Nguyen and Goldschmeding, 2008), glaucoma (Wordinger et al, 2007;Zode et al, 2009), asthma (Stumm et al, 2014) and pulmonary arterial hypertension Morrell et al, 2001). However, the mechanisms that allow the BMP pathway and the activin and TGFb pathway to antagonize one another remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Lowery

Intini

Gamer

et al. 2015

Journal of Cell Science

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Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFb signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFb signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.

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Effects of TGF-β2, BMP-4, and Gremlin in the Trabecular Meshwork: Implications for Glaucoma

Abstract: These results are consistent with the hypothesis that, in POAG, elevated expression of Gremlin by TM cells inhibits BMP-4 antagonism of TGF-beta2 and leads to increased ECM deposition and elevated IOP.

Cited by 208 publications

References 37 publications

Extracellular matrix in the trabecular meshwork

Extracellular matrix in the trabecular meshwork

Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

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