The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure.

ABSTRACT: Microfibrils are macromolecular aggregates located in the extracellular matrix of both elastic and nonelastic tissues that have essential functions in formation of elastic fibers and control of signaling through the transforming growth factor beta (TGF?) family of cytokines. Elevation of systemic TGF? and chronic activation of TGF? signal transduction are associated with diseases caused by mutations in microfibril-associated genes, including FBN1. A role for microfibrils in glaucoma is suggested by identification of risk alleles in LOXL1 for exfoliation glaucoma and mutations in LTBP2 for primary congenital glaucoma, both of which are microfibril-associated genes. Recent identification of a mutation in another microfibril-associated gene, ADAMTS10, in a dog model of primary open-angle glaucoma led us to form the microfibril hypothesis of glaucoma, which in general states that defective microfibrils may be an underlying cause of glaucoma. Microfibril defects could contribute to glaucoma through alterations in biomechanical properties of tissue and/or through effects on signaling through TGF?, which is well established to be elevated in the aqueous humor of glaucoma patients. Recent work has shown that diseases caused by microfibril defects are associated with increased concentrations of TGF? protein and chronic activation of TGF?-mediated signal transduction. In analogy with other microfibril-related diseases, defective microfibrils could provide a mechanism for the elevation of TGF?2 in glaucomatous aqueous humor. If glaucoma shares mechanisms with other diseases caused by defective microfibrils, such as Marfan syndrome, therapeutic interventions to inhibit chronic activation of TGF? signaling used in those diseases may be applied to glaucoma.

SUBMITTER: Kuchtey J 

PROVIDER: S-EPMC3991966 | biostudies-literature | 2014 Mar-Apr

REPOSITORIES: biostudies-literature