Transforming Growth Factor-β2 Induces Expression of Biologically Active Bone Morphogenetic Protein-1 in Human Trabecular Meshwork Cells

Tovar-Vidales, Tara; Fitzgerald, Ashley; Clark, Abbot F.; Wordinger, Robert J.

doi:10.1167/iovs.13-12203

Cited by 23 publications

(16 citation statements)

References 27 publications

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“…We recently reported that TM cells and tissues express BMP-1 mRNA and protein and that BMP-1 protein is induced by TGF-β2. 22 Using a LOX activity assay, we also demonstrated that secreted BMP-1 from human TM cells was biologically active and increased secreted LOX enzyme activity. Significantly, we showed that glaucomatous TM cells secreted higher levels of BMP-1 and that BMP-1 secretion in glaucomatous TM cells was further induced by exogenous TGF-β2 treatment compared to normal TM cells.…”

Section: Bone Morphogenetic Protein-1 (Procollagen C-proteinase)mentioning

confidence: 74%

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Lysyl Oxidases in the Trabecular Meshwork

Wordinger

Clark

2014

Journal of Glaucoma

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The mechanical properties of the extracellular matrix (ECM) play an important role in maintaining cellular function and overall tissue homeostasis. Emerging evidence suggests that biomechanical modifications of the ECM may be initiators and/or drivers of disease, exemplified by increased tissue stiffness. Specific ECM crosslinking enzymes (tissue transglutaminase, lysyl oxidase and lysyl oxidase-like1) are expressed in the trabecular meshwork (TM) and are regulated by transforming growth factor-beta (TGF-β isoforms. Since TGF-β isoforms are elevated in the aqueous humor (AH) of glaucoma patients, TM stiffness mediated by ECM crosslinking may be responsible for increased AH outflow resistance and elevated intraocular pressure.

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Section: Bone Morphogenetic Protein-1 (Procollagen C-proteinase)mentioning

confidence: 74%

“…Significantly, we showed that glaucomatous TM cells secreted higher levels of BMP-1 and that BMP-1 secretion in glaucomatous TM cells was further induced by exogenous TGF-β2 treatment compared to normal TM cells. 22 …”

Section: Bone Morphogenetic Protein-1 (Procollagen C-proteinase)mentioning

confidence: 99%

Lysyl Oxidases in the Trabecular Meshwork

Wordinger

Clark

2014

Journal of Glaucoma

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“…38 In addition, secreted protein acidic and rich in cysteine (SPARC), BMP1, and more related findings were proved responsible for ECM protein production and IOP upregulation. [39][40][41] To our knowledge, only several previous studies have taken advantage of miRNAs in regulating the biological behaviors of TM and offered a potential opportunity to identify biomarkers for diagnosis and prognosis of glaucoma. 27,42,43 MiR-24 can directly target 3 0 -UTR of the subtilisin-like proprotein convertase Furin, which could activate TGF-b1.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Shen

Han

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. This study investigated the effects of microRNA-483-3p (miR-483-3p) on extracellular matrix (ECM) production, and clarified the regulatory mechanism of microRNA-483-3p in human trabecular meshwork cells (HTMCs) under oxidative stress. METHODS.The expression levels of ECM (fibronectin, laminin, collagen I) in HTMCs under oxidative stress were measured by Western blot. Changes of miR-483-3p expression in HTMCs were evaluated by quantitative polymerase chain reaction (qPCR). After using lentivirus stably expressing pri-miR-483, the effects of miR-483-3p on the ECM were assessed by qPCR and Western blot. Smad4, the potential target of miR-483-3p according to mRNA target-predicting algorithms, was confirmed by luciferase assay and Western blot. Furthermore, the effects of Smad4 knockdown on ECM expression were investigated by qPCR and Western blot.RESULTS. The mRNA and protein levels of ECM (fibronectin, laminin, collagen I) were upregulated in HTMCs induced by oxidative stress. The expression level of miR-483-3p decreased in HTMCs under oxidative stress, and the ectopic expression of miR-483-3p decreased the levels of ECM. In addition, miR-483-3p targeted Smad4 through two binding sites, resulting in a decrease of Smad4 expression. Furthermore, knockdown of Smad4 reduced the levels of ECM in HTMCs.CONCLUSIONS. MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma.

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“…TGF-β1 can induce the up-regulation of several important structural ECM proteins such as collagens and fibronectin and, in general, can modulate negatively or positively the expression of a large variety of matrix proteins, proteinases (among which BMP-1 and mTLD [39,40]), proteinase inhibitors and growth factors. Even more strikingly, TGF-β1 can drastically modify the nature of the proteins expressed by a given cell type, for example through the induction of EMT (epithelial to mesenchymal transition) [41].…”

Section: Activation Of Signaling Moleculesmentioning

confidence: 99%

BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling

2015

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Bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases, here called BTPs, include the proteases originally identified for their roles in the C-terminal maturation of fibrillar procollagens ("procollagen C-proteinase"). Though numerous other substrates have since been discovered, the BTPs remain the main proteases involved in extracellular matrix assembly with little or no implication in matrix degradation. During the same period however, the BTPs have also become established as important proteases in the activation of growth factors, including TGF-β1, BMP-2/-4, GDF-8/-11 and IGFs, as well as the release of anti-angiogenic fragments from parent proteins. The BTPs are therefore key players in many pathophysiological processes such as morphogenesis, tissue repair and tumor progression. This mini-review summarizes our current knowledge of the functions of BTPs, their substrates and unusual mechanisms of regulation, and discusses their potential as new targets for future therapies.

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Transforming Growth Factor-β2 Induces Expression of Biologically Active Bone Morphogenetic Protein-1 in Human Trabecular Meshwork Cells

Abstract: BMP1 is expressed in the human TM. TGF-β2 induction of BMP1 may be responsible for increased processing of growth factors and ECM proteins into their mature forms, resulting in TM stiffness and resistance to ECM degradation.

Cited by 23 publications

References 27 publications

Lysyl Oxidases in the Trabecular Meshwork

Lysyl Oxidases in the Trabecular Meshwork

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling

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