A recent report in Glaucoma News focuses on the role of integrins in the development of fibrosis within the trabecular meshwork (TM) of the eye, shedding light on their involvement in the pathogenesis of primary open-angle glaucoma (POAG). POAG is a chronic eye disease characterized by fibrotic changes in the TM, which leads to increased tissue stiffness and elevated intraocular pressure (IOP).
The TM is a complex network of extracellular matrix (ECM) proteins, including collagens, fibronectin, laminin, and hyaluronan. Excessive remodeling of the ECM within the TM and the inner wall of Schlemm’s Canal (SC) restricts the outflow of aqueous humor, resulting in elevated IOP and the development of POAG. This remodeling can be triggered by age-related changes, elevated levels of transforming growth factor-beta 2 (TGFβ2), or other signaling cascades.
Integrins, a family of transmembrane receptors, play a crucial role in fibrosis within the TM. They regulate various signaling pathways involved in fibrosis, including TGFβ signaling, fibronectin matrix formation, myofibroblast formation, and activation of Rho GTPases. Integrins mediate cell attachment to the ECM and transduce extracellular signals into intracellular responses.
The Rho GTPase pathway, involving RhoA, Rac, and Cdc42, regulates the contractile properties of the TM and myofibroblast differentiation. Integrins control the activation and localization of Rho GTPases, affecting contractility and ECM deposition. Integrins like α5β1 and αvβ3 play critical roles in fibronectin matrix formation, which is essential for maintaining the ECM architecture during fibrosis.
Myofibroblasts, characterized by the expression of α-smooth muscle actin (α-SMA) and the presence of contractile stress fibers, contribute to fibrosis. Integrins are involved in the formation and maintenance of these stress fibers, and their contractile force generation contributes to myofibroblast transformation. Integrins also play a role in TGFβ signaling, a major driver of myofibroblast differentiation and fibrosis.
Understanding the intricate role of integrins in fibrosis is crucial for developing targeted treatments for diseases like POAG. Disrupting fibronectin fibril formation and using recombinant integrin blocking antibodies are potential approaches to mitigate fibrosis in the TM and restore its function. By targeting integrins and their associated signaling pathways, it may be possible to develop long-term antifibrotic strategies for chronic fibrotic diseases, including POAG.
In conclusion, integrins play a significant role in the development of fibrosis within the TM and are involved in various stages of fibrotic processes. Targeting integrins and their associated signaling pathways holds promise for the treatment of diseases like POAG, aiming to restore TM homeostasis and improve the quality of life for affected individuals. The study findings were published in the peer-reviewed journal Frontiers in Ophthalmology.