Extracellular Matrix Remodeling in the Retina and Optic Nerve of a Novel Glaucoma Mouse Model

Abstract

Glaucoma is a neurodegenerative disease that is characterized by the loss of retinal ganglion cells (RGC) and optic nerve fibers. Increased age and intraocular pressure (IOP) elevation are the main risk factors for developing glaucoma. Mice that are heterozygous (HET) for the mega-karyocyte protein tyrosine phosphatase 2 (PTP-Meg2) show chronic and progressive IOP elevation, severe RGCs loss, and optic nerve damage, and represent a valuable model for IOP-dependent primary open-angle glaucoma (POAG). Previously, evidence accumulated suggesting that glaucomatous neurodegeneration is associated with the extensive remodeling of extracellular matrix (ECM) molecules. Unfortunately, little is known about the exact ECM changes in the glaucomatous retina and optic nerve. Hence, the goal of the present study was to comparatively explore ECM alterations in glaucomatous PTP-Meg2 HET and control wild type (WT) mice. Due to their potential relevance in glaucomatous neurodegeneration, we specifically analyzed the expression pattern of the ECM glycoproteins fibronectin, laminin, tenascin-C, and tenascin-R as well as the proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) family. The analyses were carried out in the retina and optic nerve of glaucomatous PTP-Meg2 HET and WT mice using quantitative real-time PCR (RT-qPCR), immunohistochemistry, and Western blot. Interestingly, we observed increased fibronectin and laminin levels in the glaucomatous HET retina and optic nerve compared to the WT group. RT-qPCR analyses of the laminins α4, β2 and γ3 showed an altered isoform-specific regulation in the HET retina and optic nerve. In addition, an upregulation of tenascin-C and its interaction partner RPTPβ/ζ/phosphacan was found in glaucomatous tissue. However, comparable protein and mRNA levels for tenascin-R as well as aggrecan and brevican were observed in both groups. Overall, our study showed a remodeling of various ECM components in the glaucomatous retina and optic nerve of PTP-Meg2 HET mice. This dysregulation could be responsible for pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration.

Knock-Out of Tenascin-C Ameliorates Ischemia-Induced Rod-Photoreceptor Degeneration and Retinal Dysfunction

“…Elevated Tnc expression could also be observed in the optic nerve head of patients with primary open-angle glaucoma (Pena et al, 1999). In a previous study, we also verified an upregulation of Tnc, and its interaction partner the chondroitin sulfate proteoglycan phosphacan in an experimental autoimmune and an IOP-dependent glaucoma mouse model (Reinehr et al, 2016;Reinhard et al, 2021). Immunized Tnc KO mice exhibit a reduced retinal ganglion cell loss and an enhanced anti-inflammatory cytokine expression (Wiemann et al, 2020), suggesting that Tnc deficiency provides various neuroprotective effects.…”

“…A significant increase of Tnc immunoreactivity was found in an experimental autoimmune glaucoma model at 7 and 14 days, whereas no differences were observed at a later point in time ( Reinehr et al, 2016 ). In an IOP-dependent glaucoma model, however, we recently observed increased Tnc levels a few weeks after IOP elevation ( Reinhard et al, 2021 ), which suggests that Tnc expression depends not only on the time, but also on the type of retinal damage. In an I/R rat model, we detected diminished levels of Tnc at 21 days post-ischemia.…”

Damage-Associated Molecular Patterns (DAMPs) in Retinal Disorders

“…Interestingly, a significant decrease in aggrecan was found in the optic nerve head of glaucomatous eyes compared to control eyes of non-human primates [ 61 ]. However, such findings were absent in rodent models [ 62 ]. A significant increase in phosphacan levels was also observed in an autoimmune glaucoma rat model, with studies indicating its role in disease progression [ 62 , 78 ].…”

“…However, such findings were absent in rodent models [ 62 ]. A significant increase in phosphacan levels was also observed in an autoimmune glaucoma rat model, with studies indicating its role in disease progression [ 62 , 78 ]. There was a significant increase in chondroitin sulfate and HS in serum and optic nerve heads of glaucoma patients [ 63 ].…”

Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration

“…In our experience, we observe negligible spontaneous donor human RGC integration into the host RGCL when the ILM remains intact, whereas somal integration is greatly enhanced by enzymatic disruption of ILM [16], suggesting the inner retinal extracellular matrix is a significant structural barrier to transplanted RGCs integration. A chronic progressive mouse model of glaucoma demonstrated pathologic retinal ECM remodeling and upregulation of several families of glycoproteins, including laminin and fibronectin [152]. Together with evidence that ECM alterations impact endogenous RGC survival during optic neuropathy disease progression [153], the interactions between ECM and donor RGCs for both survival and migration must be considered.…”