Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure

Wan-Heng Wang; Loretta G McNatt; Iok-Hou Pang; J Cameron Millar; Peggy E Hellberg; Mark H Hellberg; H Thomas Steely; Jeffrey S Rubin; John H Fingert; Val C Sheffield; Edwin M Stone; Abbot F Clark

doi:10.1172/JCI33871

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Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure

Journal article

Open access

Peer reviewed

Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure

Wan-Heng Wang, Loretta G McNatt, Iok-Hou Pang, J Cameron Millar, Peggy E Hellberg, Mark H Hellberg, H Thomas Steely, Jeffrey S Rubin, John H Fingert, Val C Sheffield, …

The Journal of clinical investigation, Vol.118(3), pp.1056-1064

03/2008

DOI: 10.1172/JCI33871

PMCID: PMC2242621

PMID: 18274669

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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.

Amino Acid Sequence

Signal Transduction

Glycogen Synthase Kinase 3 - antagonists & inhibitors

Intraocular Pressure

Membrane Proteins - genetics

Humans

Cells, Cultured

Intercellular Signaling Peptides and Proteins - genetics

Molecular Sequence Data

RNA, Messenger - analysis

Glycogen Synthase Kinase 3 beta

Intercellular Signaling Peptides and Proteins - physiology

Animals

Membrane Proteins - physiology

Trabecular Meshwork - metabolism

Mice

Mice, Inbred BALB C

beta Catenin - physiology

Wnt Proteins - antagonists & inhibitors

Glaucoma - physiopathology

Details

Title: Subtitle: Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure
Creators: Wan-Heng Wang - Alcon Research Ltd., Fort Worth, Texas 76134, USA
Loretta G McNatt
Iok-Hou Pang
J Cameron Millar
Peggy E Hellberg
Mark H Hellberg
H Thomas Steely
Jeffrey S Rubin
John H Fingert
Val C Sheffield
Edwin M Stone
Abbot F Clark
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.118(3), pp.1056-1064
DOI: 10.1172/JCI33871
PMID: 18274669
PMCID: PMC2242621
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: United States
Grant note: Intramural NIH HHS
Language: English
Date published: 03/2008
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983980091102771

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