BIOMECHANICAL PROPERTIES OF THE TRABECULAR MESHWORK

GUEST AUTHOR

JUWAIRIYA ILYAS

Ajmal Khan Tibbiya College

Aligarh Muslim University

Aligarh- India

Cells forming the trabecular meshwork (TM) contain thick bundles of actin in their cytoplasm.

These actin filaments have a number of functions: 1.       Responsible for motile events in the cell. 2.       Contribute to cytoskeletal framework of the cell. 3.       Modulate aqueous humor outflow. 4.       Control cell shape, adherence to the extracellular matrix, cytokinesis and phagocytic activity. 5.       Regulate protein synthesis. 6.       Provide a contractile apparatus for lifting of the trabecular sheets.

Cytoskeletal elements can be divided into 3 major classes: 1.       Microfilaments 2.       Microtubules 3.       Intermediate filaments

The TM is anchored by ciliary muscle tendons and fine elastic fibers which connect it to the endothelium of the Schlemm’s Canal (SC).

The ciliary muscle contracts and relaxes to alter the shape of TM and modify aqueous humor outflow through the TM and SC.

Ciliary muscle contraction causes widening of intracellular spaces in TM which increase permeability of tissues with simultaneous decrease in uveoscleral outflow.

The aqueous humor outflow between conventional and unconventional pathway gets distributed depending on the tone of the ciliary muscle.

This hydraulic like system also influences cellular responses, particularly of actin cytoskeleton.

CLANs (Cross-linked-actin-network): They are complex polygons of actin which are developed when human TM cultures are exposed to dexamethasone.

CLAN has a central hub, known as vertisome. It radiates at least 5 thin spokes or actin filament bundles, which connect it to adjacent hubs.

Some CLAN like structures (network CLAN, basket CLAN or starbursts) are also described in recent studies.

Uveal and corneo-scleral regions have more CLAN and CLAN-like structures compared to juxtacanalicular TM regions.

CLAN hub sites are rich in α-actinin which is an actin cross-linking and molecular scaffold protein. It has the following functions:

1.       Link plasma membrane to actin cytoskeleton.

2.       Determine cell shape.

3.       Arrange transmembrane protein and organize organelles.

The hub also has Syndecan-4.

It is a transmembrane heparin sulfate proteoglycan.

Syndecan-4 interacts with actin and acts as a receptor in intracellular signaling.

The significance of CLANs and their mechanism of formation in health and disease is still unknown. CLANs are the most stable form of microfilaments in the cell and may have important functional roles.

In normal conditions cells contain F-actin in 2 common patterns: 1.       Diffuse arrangement, which forms a tightly packed bundle called “stress fibers’. 2.       Polygonal arrangement- which forms a geodesic dome-like structure. These structures have intrinsic rigidity and contribute to cellular tensegrity. In glaucoma, F-actin arrangement in innerwall and juxtacanalicular cells of outflow system get disturbed.

With increase in IOP mechanical stress is put on trabecular structures. Due to this stress, elastin within collagen beams and elastic-like network of juxtacanalicular cells undergoes mechanical strain. Increase in IOP causes mechanical stretching (strain) of TM (and it returns back to normal once the IOP goes back to normal levels). When IOP increases, the increased mechanical stretch of TM is transduced to extracellular matrix through integrin mediated attachments. Any deformity in TM makes the extracellular matrix more permeable to aqueous flow which increases the outflow facility.

The following are some agents which may be a new class of anti-glaucoma medications:

H7: It is a serine-threonine kinase inhibitor which blocks actinomyosin contractility and increases aqueous humor outflow. Ethacrynic acid: It causes reversible cell-shape changes in TM. It is associated with disruption of many components like F-actin, α-actinin, vinculin and vimentin. Latrunculins and cytochalasins: They directly or indirectly disrupt F-actin, alter cytoskeletal function and thus, increase outflow facility.

Rho/ROCK is a kinase which belongs to AGC family of serine threonine kinases. “Rho” plays a critical role in signaling pathway, which leads to the formation of actin stress fibers and local adhesions. Rho regulates the movement and shape of cells by acting on the actin cytoskeleton. ROCK is of 2 types: 1.       ROCK 1 2.       ROCK 2 Human ROCK 1 is a major downstream effector of small GTPase Rho-A. Rat ROCKs were found to be the first effectors of Rho and by phosphorylation of Myosin Light Chain, induce formation of stress fibers and focal adhesions. With this phosphorylation, actin binds to myosin II and contractility increases. Rho/ROCK pathway plays an important role in: 1.       Modulation of cytoskeletal integrity of cells. 2.       Synthesis of extracellular material components in the aqueous humor outflow tissues. 3.       Permeability of SC endothelial cells. Rho/ROCK pathway has been found in cells of TM, juxtacanalicular cells and SC. It is hypothesized that in glaucomatous eyes there is increased expression of Rho/ROCK pathway.

Drainage of aqueous through the conventional pathway is affected by: 1.       Abnormal accumulation of extracellular matrix (ECM hypothesis) 2.       Changes in the contractile activity and cell adhesive interactions of aqueous outflow pathway (Contractility hypothesis). TM cells exhibit a smooth muscle-like phenotype-based on their expression of various smooth muscle specific proteins such as: 1.       α-smooth muscle actin (α-SMA). 2.       CPA-17 (protein kinase-C potentiated protein phosphatase-1 inhibitor protein). Focal contacts, adherens cell-cell junction and bundles of microfilaments are numerous microfilament based structures found in cells of outflow pathway.