The Role of Autotaxin in Lamina Cribrosa Cells in Glaucoma

Glaucoma is the leading cause of irreversible blindness worldwide. Current medical and surgical therapies do not directly target the mechanisms underlying glaucoma pathogenesis. In primary open angle glaucoma, extracellular matrix remodeling and fibrosis in both the trabecular meshwork and the lamina cribrosa of the optic nerve head is observed. These pathological changes result in elevated intraocular pressure, and visual field defects due to retinal ganglion cell death, respectively. Identification of biochemical pathways resulting in both trabecular meshwork and lamina cribrosa remodeling is therefore crucial. The lysophosphatidic acid (LPA) axis has been implicated in wound healing, as well as many forms of pathological fibrosis. Among these are pulmonary fibrosis, cancers, and glaucoma. LPA, its receptors, and the enzyme responsible for its synthesis known as autotaxin, have all been found to be upregulated in the anterior chamber in glaucoma. There is very little known about the role of autotaxin and LPA in the optic nerve head in glaucoma, and nothing published on this pathway in lamina cribrosa specifically. The aim of this thesis was to investigate the role of the LPA axis, including autotaxin, in the lamina cribrosa in glaucoma. We cultured lamina cribrosa cells from age-matched normal and glaucoma patient donors. We assessed differential gene and protein expression of components of the LPA axis via polymerase chain reaction, immunofluorescence, and western blotting. We found that the LPA receptors were all upregulated in glaucoma versus normal, and autotaxin was significantly upregulated at both RNA and protein levels. Glaucoma lamina cribrosa cells possessed higher autotaxin activity on a functional assay. We treated glaucoma lamina cribrosa cells with an inhibitor of autotaxin to decrease LPA production and showed that this resulted in significantly decreased expression of extracellular matrix components and reduced proliferation rate of lamina cribrosa cells. Our work strongly supports a role for autotaxin and the LPA axis in the lamina cribrosa of the optic nerve head in glaucoma. Autotaxin inhibition is a potential pharmacological strategy to halt extracellular matrix remodeling in glaucoma.