title: Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure.
abstract: 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 beta-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.
authors.affiliation: Alcon Research Ltd., Fort Worth, Texas 76134, USA.
authors.forename: Wan-Heng
authors.initials: WH
authors.lastname: Wang
authors.forename: Loretta G
authors.initials: LG
authors.lastname: McNatt
authors.forename: Iok-Hou
authors.initials: IH
authors.lastname: Pang
authors.forename: J Cameron
authors.initials: JC
authors.lastname: Millar
authors.forename: Peggy E
authors.initials: PE
authors.lastname: Hellberg
authors.forename: Mark H
authors.initials: MH
authors.lastname: Hellberg
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Steely
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
authors.forename: John H
authors.initials: JH
authors.lastname: Fingert
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005901:Glaucoma / Q000503:physiopathology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007429:Intraocular Pressure; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014129:Trabecular Meshwork / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins