Transforming growth factor-beta-regulated gene transcription and protein expression in human GFAP-negative lamina cribrosa cells
| Autor: | Madeline Murphy, Martin O. Leonard, Ruaidhrí P. Kirwan, Colm O'Brien, Abbot F. Clark |
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| Rok vydání: | 2005 |
| Předmět: |
Transcriptional Activation
medicine.medical_specialty genetic structures Decorin medicine.medical_treatment Optic Disk Nerve Tissue Proteins SMAD Polymerase Chain Reaction Extracellular matrix Cellular and Molecular Neuroscience Transforming Growth Factor beta Internal medicine Glial Fibrillary Acidic Protein medicine Humans RNA Messenger Regulatory Elements Transcriptional Growth Substances Cells Cultured Oligonucleotide Array Sequence Analysis Glial fibrillary acidic protein biology Growth factor Biglycan Gene Expression Profiling Fibrosis eye diseases Cell biology Extracellular Matrix Up-Regulation CTGF Endocrinology Neurology Gene Expression Regulation biology.protein sense organs Neuroglia Glaucoma Open-Angle Transforming growth factor |
| Zdroj: | Glia. 52(4) |
| ISSN: | 0894-1491 |
| Popis: | Primary open-angle glaucoma (POAG) is a progressive optic neuropathy, which is a major cause of worldwide visual impairment and blindness. Pathological hallmarks of the glaucomatous optic nerve head (ONH) include retinal ganglion cell axon loss and extracellular matrix (ECM) remodeling of the lamina cribrosa layer. Transforming growth factor-beta (TGF-beta) is an important pro-fibrotic modulator of ECM metabolism, whose levels are elevated in human POAG lamina cribrosa tissue compared with non-glaucomatous controls. We hypothesize that in POAG, lamina cribrosa (LC) glial cells respond to elevated TGF-beta, producing a remodeled ONH ECM. Using Affymetrix microarrays, we report the first study examining the effect of TGF-beta1 on global gene expression profiles in glial fibrillary acidic acid (GFAP)-negative LC glial cells in vitro. Prominent among the differentially expressed genes were those with established fibrogenic potential, including CTGF, collagen I, elastin, thrombospondin, decorin, biglycan, and fibromodulin. Independent TaqMan and Sybr Green quantitative PCR analysis significantly validated genes involved in regulation of cell proliferation (platelet-derived growth factor [PDGF-alpha]), angiogenesis (vascular endothelial growth factor [VEGF]), ECM accumulation and degradation (CTGF, IL-11, and ADAMT-S5), and growth factor binding (ESM-1). Bioinformatic analysis of the ESM-1 promoter identified putative Smad and Runx transcription factor binding sites, and luciferase assays confirmed that TGF-beta1 drives transcription of the ESM-1 gene. TGF-beta1 induces expression and release of ECM components in LC cells, which may be important in regulating matrix remodeling in the lamina cribrosa. In disease states such as POAG, the LC cell may represent an important pro-fibrotic cell type and an attractive target for novel therapeutic strategies. |
| Databáze: | OpenAIRE |
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