What is the role of the extracellular network in glaucoma?

From the Guidelines

The extracellular network plays a crucial role in glaucoma pathogenesis by contributing to increased intraocular pressure and optic nerve damage, and its remodeling is a key target for therapeutic approaches. In glaucoma, abnormal extracellular matrix (ECM) remodeling occurs in the trabecular meshwork, which impedes aqueous humor outflow and raises intraocular pressure 1. The ECM components, including collagens, elastin, fibronectin, and glycosaminoglycans, undergo structural and compositional changes that increase outflow resistance. Additionally, the ECM surrounding retinal ganglion cells and their axons in the optic nerve head becomes altered, contributing to mechanical stress and impaired axonal transport. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) become dysregulated, further disrupting ECM homeostasis. These ECM changes also affect cellular signaling pathways and mechanotransduction, influencing cell survival and function. Understanding these ECM alterations has led to therapeutic approaches targeting ECM remodeling, including rho kinase inhibitors like netarsudil, which reduce ECM production and cell contractility to improve outflow facility. Prostaglandin analogs like latanoprost also work partly by inducing MMPs to remodel the ECM and enhance uveoscleral outflow.

Some key points to consider in the management of glaucoma include:

• Educating patients about the disease process, treatment options, and potential risks and benefits 1
• Encouraging patients to report any changes in their condition or concerns about their treatment 1
• Considering the impact of glaucoma on patients' quality of life, including their visual function, emotional well-being, and social interactions 1
• Referring patients to specialized care or vision rehabilitation services as needed 1

Overall, the extracellular network plays a critical role in the pathogenesis of glaucoma, and its remodeling is a key target for therapeutic approaches. By understanding the changes that occur in the ECM and how they contribute to the development of glaucoma, clinicians can provide more effective treatment and management options for patients with this condition.

From the Research

Role of Extracellular Network in Glaucoma

The extracellular network plays a significant role in glaucoma, with various studies highlighting its importance in the disease's progression. Some key points to consider:

• The extracellular matrix (ECM) is involved in the regulation of intraocular pressure (IOP), which is a primary risk factor for glaucoma 2.
• Changes in the ECM of the trabecular meshwork (TM) have been observed in glaucoma, including increased stiffness and ultrastructural changes 2.
• The ECM in the lamina cribrosa region of the optic nerve head (ONH) also undergoes changes, including thickening and posterior migration, leading to a thin fibrotic connective tissue structure/scar 3.
• The extracellular network is also involved in the remodeling of ECM components in the glaucomatous retina and optic nerve, including the upregulation of fibronectin, laminin, and tenascin-C 4.

ECM Remodeling in Glaucoma

ECM remodeling is a key aspect of glaucomatous neurodegeneration, with various studies highlighting the changes that occur in the ECM of the retina and optic nerve. Some key points to consider:

• The expression of ECM glycoproteins, such as fibronectin and laminin, is increased in the glaucomatous retina and optic nerve 4.
• The proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) family are also involved in ECM remodeling in glaucoma 4.
• The dysregulation of ECM components can lead to pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration 4.

Clinical Implications

The role of the extracellular network in glaucoma has significant clinical implications, particularly in the development of new treatments for the disease. Some key points to consider:

• Current treatments for glaucoma focus on reducing IOP, but do not address the underlying changes in the ECM 5.
• New pharmacologic medications, such as antiglaucomatous agents and neuroprotective molecules, are being developed to target the ECM and prevent or slow down disease progression 6.
• Understanding the roles of the extracellular network in glaucoma can provide new insights into the development of effective treatments for the disease 6, 3, 4, 2.