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 (TGFb) family of cytokines. Elevation of systemic TGFb and chronic activation of TGFb 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 microfibrilassociated genes.

Definition, Classification, and Pathophysiology of Canine Glaucoma

“…This mutation found in beagles affected with POAG would support an altered processing of ECM and/or defects in microfibril structure that would eventually contribute to a decreased outflow and subsequently to an increased intraocular pressure. 31,82 …”

“…The nonpigmented ciliary epithelium, the microfibrils of the zonule, and the ones surrounding the elastin core in the ECM are the major sites for storage. 82 Activation of TGFb2 is induced by other proteins, among which plasmin and matricellular thrombospondin-1 (TSP1) are the most important. 166,167 However, membrane receptors are necessary to activate the intracellular signals for production of ECM proteins.…”

Genetics of Canine Primary Glaucomas

“…These so-called microfibrillopathies include Weill-Marchesani syndrome (WMS) and Marfan syndrome (MS) and are caused by mutations in genes responsible for normal microfibril formation, most importantly ADAMTS10, ADAMTS17, and fibrillin-1 (FBN1), resulting in defective microfibrils. [78][79][80][81][82][83][84] Similar to variations of canine POAG and PLL, the ocular phenotype of WMS/MS in human patients is characterized by ectopia lentis/PLL, which can occur in combination with either POAG or PACG, the latter caused by a shallow anterior chamber and pupillary block from anterior dislocation of the lens. 78,[80][81][82][84][85][86][87][88] The accumulation of plaques within the trabecular meshwork has been well documented in eyes of humans and beagles with POAG; these plaques may contain FBN1 and are likely responsible for increased aqueous humor outflow resistance.…”

“…[78][79][80][81][82][83][84] Similar to variations of canine POAG and PLL, the ocular phenotype of WMS/MS in human patients is characterized by ectopia lentis/PLL, which can occur in combination with either POAG or PACG, the latter caused by a shallow anterior chamber and pupillary block from anterior dislocation of the lens. 78,[80][81][82][84][85][86][87][88] The accumulation of plaques within the trabecular meshwork has been well documented in eyes of humans and beagles with POAG; these plaques may contain FBN1 and are likely responsible for increased aqueous humor outflow resistance. 67,70,[89][90][91][92][93] To the best of the authors' knowledge, POAG-and PLL-affected dogs do not show any of the systemic changes seen in human patients with WMS/MS, such as skeletal abnormalities and cardiovascular defects.…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…There are, however, several genetic variants within the collagen genes that are significantly associated with glaucomatous endophenotypes such as maximum vertical cup-disc ratio, increased optic disc cup area and altered central corneal thickness [29][30][31][32]. Other mutations within fibrillin 1, latent-transforming growth factor beta-binding protein 2 and versican genes have been associated with glaucoma in humans [33][34][35][36][37]. These proteins constitute large ECM fibrils that have roles in cell adhesion within the matrix.…”