title: Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork.
abstract: The most critical risk factor for optic nerve damage in cases of primary open-angle glaucoma (POAG) is an increased intraocular pressure (IOP) caused by a resistance to aqueous humor outflow in the trabecular meshwork (TM). The molecular pathogenesis of this increase in outflow resistance in POAG has not yet been identified, but it may involve transforming growth factor TGF-β2, which is found in higher amounts in the aqueous humor of patients with POAG. Connective tissue growth factor (CTGF) is a TGF-β2 target gene with high constitutive TM expression. In this study, we show that either adenoviral-mediated or transgenic CTGF overexpression in the mouse eye increases IOP and leads to optic nerve damage. CTGF induces TM fibronectin and α-SMA in animals, whereas actin stress fibers and contractility are both induced in cultured TM cells. Depletion of CTGF by RNA interference leads to a marked attenuation of the actin cytoskeleton. Rho kinase inhibitors cause a reversible decline in the IOP of CTGF-overexpressing mice to levels seen in control littermates. Overall, the effects of CTGF on IOP appear to be caused by a modification of the TM actin cytoskeleton. CTGF-overexpressing mice provide a model that mimics the essential functional and structural aspects of POAG and offer a molecular mechanism to explain the increase of its most critical risk factor.
authors.affiliation: Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Junglas
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kuespert
authors.forename: Amin A
authors.initials: AA
authors.lastname: Seleem
authors.forename: Tobias
authors.initials: T
authors.lastname: Struller
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ullmann
authors.forename: Michael
authors.initials: M
authors.lastname: Bösl
authors.forename: Anja
authors.initials: A
authors.lastname: Bosserhoff
authors.forename: Josef
authors.initials: J
authors.lastname: Köstler
authors.forename: Ralf
authors.initials: R
authors.lastname: Wagner
authors.forename: Ernst R
authors.initials: ER
authors.lastname: Tamm
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fuchshofer
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure*; D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005902:Glaucoma, Open-Angle / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008875:Middle Aged; D009901:Optic Nerve Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; C526318:CCN2 protein, mouse; D005353:Fibronectins; D055513:Connective Tissue Growth Factor