Myocilin Regulation by Brain-Derived Neurotophic Factor and Transforming Growth Factor-Beta2 in Normal and Glaucomatous Human Trabecular Meshwork Cells

Liu, Xiaochun, Myocilin Regulation by Brain-derived Neurotrophic Factor and Transforming Growth Factor beta2 in Normal and Glaucomatous Human Trabecular Meshwork. Doctor of Philosophy (Biomedical Sciences), May 2003, 119 pp., 3 tables, 26 illustrations, bibliography, 188 titles. Glaucoma, of which primary open-angle glaucoma (POAG) is the most common form, is the second leading cause of irreversible blindness in the world. Ocular hypertension is an important risk factor in the development of POAG. The human trabecular meshwork (HTM) is the major regulation site for aqueous humor outflow thus controlling intraocular pressure. In POAG, there are specific morphological and pathological changes in the HTM, including an increase in extracellular matrix components and a decrease in the number of HTM cells. Myocilin (also known as GLC1A or TIGR) is associated with hypertensive POAG by both genetic linkage analysis and glucocorticoid induction studies. Brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta isoforms (TGFβ1-3) have been shown to be present both in normal cultured HTM cells and aqueous humor. In addition, biologically active TGFβ2 levels are increased in the aqueous humor of POAG patients. Mechanical stretch, an important factor in HTM during intraocular hypertension, may up-regulate the expression of BDNF in the HTM cells. Therefore, BDNF and TGFβ2 may be modulators of extracellular proteins in response to the hypertensive glaucomatous injury. However, the regulation of myocilin expression by these growth factors in the HTM has not been studied. Moreover, HTM cells may signal each other via paracrine and autocrine pathways involving BDNF and TGFβ2. In this study, HTM cells were isolated and cultured in vitro. Myocilin gene expression and protein secretion by normal and glaucomatous HTM cells were compared. The regulatory effects of BDNF and/or TGFβ2 or myocilin gene expression and protein secretion by normal and glaucomatous HTM cells were also examined, as well as the reciprocal induction between BDNF and TGFβ2 gene expression and protein secretion. The interdependence between BDNF and TGFβ2 in regulating myocilin expression was determined. The results of the study established the regulatory effects of BDNF and TGFβ2 on myocilin expression as well as on each other. It is possible that both BDNF and TGFβ2 interact with each other in response to an increase of intraocular pressure through paracrine/autocrine mechanisms, resulting in differential gene expression of myocilin.