Remodeling of the Lamina Cribrosa: Mechanisms and Potential Therapeutic Approaches for Glaucoma

Abstract

Glaucomatous optic neuropathy is the leading cause of irreversible blindness in the world. The chronic disease is characterized by optic nerve degeneration and vision field loss. The reduction of intraocular pressure remains the only proven glaucoma treatment, but it does not prevent further neurodegeneration. There are three major classes of cells in the human optic nerve head (ONH): lamina cribrosa (LC) cells, glial cells, and scleral fibroblasts. These cells provide support for the LC which is essential to maintain healthy retinal ganglion cell (RGC) axons. All these cells demonstrate responses to glaucomatous conditions through extracellular matrix remodeling. Therefore, investigations into alternative therapies that alter the characteristic remodeling response of the ONH to enhance the survival of RGC axons are prevalent. Understanding major remodeling pathways in the ONH may be key to developing targeted therapies that reduce deleterious remodeling.

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

“…A reduction in intraocular pressure remains the only proven treatment for POAG, but it does not prevent further neurodegeneration. In their review, Strickland et al [ 7 ] discuss the three major classes of cells in the human optic nerve head (ONH) that provide support for the lamina cribrosa, lamina cribrosa (LC) cells, glial cells, and scleral fibroblasts, all of which are essential in maintaining healthy RGC axons and demonstrate responses to glaucomatous conditions through extracellular matrix remodeling. The authors discuss these responses and emphasize that understanding the major remodeling pathways in the ONH may be key to developing targeted therapies that reduce deleterious remodeling.…”

Transcriptomic Analysis of the Ocular Posterior Segment Completes a Cell Atlas of the Human Eye

“…Increased pressure leads to stress on the PPS and ONH, resulting in reactions of astrocytes and other cells in the lamina cribrosa (LC), a sieve-like structure in the ONH through which RGC axons pass (Fig. 1B) (21)(22)(23). These reactions, along with remodeling of the extracellular matrix, cause or exacerbate compression of RGC axons.…”

“…These reactions, along with remodeling of the extracellular matrix, cause or exacerbate compression of RGC axons. The compression then leads to dysfunction and eventual death of the RGCs which is the proximate cause of glaucomatous vision loss (7,21,24). To date, at least 13 genes have been associated with early onset or congenital forms of glaucoma (21,(25)(26)(27)(28)(29).…”

“…The compression then leads to dysfunction and eventual death of the RGCs which is the proximate cause of glaucomatous vision loss (7,21,24). To date, at least 13 genes have been associated with early onset or congenital forms of glaucoma (21,(25)(26)(27)(28)(29). In addition, large GWAS meta-analyses have associated 127 genomic loci with primary open angle glaucoma (POAG; the most common late onset form of glaucoma), and 112 loci with IOP (30,31).…”

The Fibro-Inflammatory Response in the Glaucomatous Optic Nerve Head

“…The main function of the LC cells is to secret ECM proteins such as collagens, elastin, and fibronectin, to maintain the structural laminar beams that physically support the exiting RGC axons [48]. LC cells are highly responsive to chemical and mechanical stimuli, altering their gene expression levels when exposed to transforming growth factors (TGFs), known to be involved in ocular wound healing and glaucoma pathophysiology, or under mechanical strain [49][50][51][52][53].…”