Damage within trabecular meshwork in glaucoma better understood

February 15, 2012
Lynda Charters

The trabecular meshwork fails in glaucoma because of physical changes in the trabecular meshwork and altered signaling pathways.

Key Points

Orlando, FL-The trabecular meshwork fails in glaucoma because of physical changes in the trabecular meshwork and altered signaling pathways. Abbot F. Clark, PhD, explained the mechanism by which the damage occurs during Glaucoma Subspecialty Day at the annual meeting of the American Academy of Ophthalmology. "The trabecular meshwork cells make and maintain the sheets and beams of the trabecular meshwork and provide natural resistance to aqueous humor outflow," said Dr. Clark, director, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth. "The cells are also highly phagocytic and therefore a self-cleaning filter."

Morphologic changes

Evidence suggests that the trabecular meshwork fails in glaucoma. W. Morton Grant, MD, published evidence as early as 1951 showing that the IOP becomes elevated as a result of decreased outflow of the aqueous humor. When eyes with primary open-angle glaucoma (POAG) are compared with normal eyes, there is a dramatic difference in the outflow facility in the glaucomatous eyes. The elevation in IOP is associated with morphologic and chemical changes in the trabecular meshwork, Dr. Clark explained.

The cells in the trabecular meshwork decrease during the normal aging process, but glaucoma exacerbates the cell loss. In addition to deposition of plaque-like material, there is increased fibronectin and transglutaminase (TGM2), an enzyme that cross-links the ECM and makes it more resistant to degradation, according to Dr. Clark.

The actin cytoskeleton in the trabecular meshwork cells becomes reorganized during the glaucomatous process to form cross-linked actin networks.

There is also evidence that oxidation affects the trabecular meshwork with normal aging, but this seems to be exacerbated in the trabecular meshwork in glaucomatous eyes. There is evidence of genomic DNA and mitochondrial damage and mitochondrial defects, he noted.

Signaling pathways

"There is currently a lot of excitement because of a better understanding of pathogenic signaling pathways," Dr. Clark said.

For example, glucocorticoid therapy can cause the IOP to increase in secondary OAG in susceptible individuals, and the glucocorticoids have been implicated in POAG. Dr. Clark and colleagues found an alternative splice of the glucocorticoid receptor, glucocorticoid receptor beta (GRβ), that regulates glucocorticoid activity in the trabecular meshwork. In normal trabecular meshwork cells, GRβ expression is high but at lower levels in glaucomatous trabecular meshwork cells, which are more sensitive to glucocorticoids.

The first glaucoma gene that was identified is myocilin (."We know that glaucoma mutations lead to nonsecretion of myocilin and protein stress in the trabecular meshwork cells," he explained. A transgenic mouse model {MYOC ( developed at the University of Iowa expresses a mutant form of human myocilin, which is not secreted into the aqueous humor and causes protein stress.

A chemical chaperone (PBA) that refolds myocilin then allows it to be secreted into the aqueous humor and in turn decreases protein stress in the trabecular meshwork of the MYOC Tg mouse model.

Not only does it increase secretion of myocilin and reduce protein stress, but the transgenic mouse has many features of POAG, such as elevated IOP, decreased ganglion cells, damage to the axons of the optic nerve, and loss of visual function. These are all restored by the chemical chaperone, he noted.

Another signaling pathway that is implicated in glaucoma development is transforming growth factor β2 (TGFβ2). This is one of the growth factors that is elevated in POAG in the aqueous humor and the trabecular meshwork in patients with glaucoma. According to Dr. Clark, TGFβ2 promotes deposition of ECM in the trabecular meshwork and by itself can cause elevation of the IOP in perfuse culture and rodent eyes.

The mechanism of the IOP increase with TGFβ2 is deposition of the ECM in the trabecular meshwork, which is accomplished in three ways: increased ECM synthesis, increased ECM cross-linking, and decreased ECM turnover. TGFβ2 also causes changes in the actin cytoskeleton.

BMP is another signaling pathway that is involved in glaucoma development. Gremlin, a BMP antagonist, is expressed highly in glaucomatous trabecular meshwork. Gremlin itself can elevate the IOP in perfusion-cultured eyes, Dr. Clark explained.

"There is interaction between the BMP signaling pathway and the TGFβ signaling pathway," he said.

Dr. Clark discussed a final pathogenic pathway, the Wnt signaling pathway. Secreted frizzled related protein (SFRP1) is the Wnt antagonist and its expression is elevated in glaucoma. Dr. Clark recounted that elevated expression increased the IOP in mice.

"The trabecular meshwork fails in glaucoma as a result of physical changes in the trabecular meshwork characterized by progressive loss of trabecular meshwork cells, changes in the ECM and cytoskeleton, and oxidative and mitochondrial damage," Dr. Clark concluded. "Altered signaling pathways also cause the trabecular meshwork to fail, e.g., MYOC and proteins tress, altered GR isoforms, TGFβ and gremlin, and SFRP1, which will be subjects of future studies."

FYI

Abbot F. Clark, PhD
E-mail: Abe.Clark@unthsc.edu

Dr. Clark receives grant support from Alcon Laboratories.

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