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Editors Selection IGR 15-2
Basic Science: Gene studies and glaucoma pathogenesis
Comment by James Tan on:
53825 Substratum stiffness and latrunculin B modulate the gene expression of the mechanotransducers YAP and TAZ in human trabecular meshwork cells, Thomasy SM; Morgan JT; Wood JA et al., Experimental Eye Research, 2013; 113: 66-73
Thomasy et al. explore the role of tissue stiffness and actin cytoskeleton modulation in trabecular meshwork (TM) mechanotransduction. Mechanotransduction is the process by which cells convert mechanical stimuli into signals that lead to tissue responses. It allows cells to sense physical features of their environment such as stress, strain, pressure, movement and substrate rigidity. The overarching idea here is that TM cells sense and respond to their physical environment in a way that affects tissue mechanics, intraocular pressure and glaucoma pathogenesis.
The authors studied gene expression of YAP and TAZ, two regulatory proteins concerned with sensing substratum stiffness, a surrogate of TM extracellular matrix (ECM) stiffness that apparently increases in glaucoma. Human TM cells from three separate donors were cultured on gels of different stiffness to simulate this disease effect. Latrunculin B, an actin-modulating agent, is a novel glaucoma drug in clinical trials. Effect of Latrunculin B on YAP- and TAZ-mediated mechanosensing was analyzed in relation to substrate stiffness and gene and protein expression.
The authors found that YAP and TAZ gene expression were significantly affected by a stiffer gel substrate based on quantitative mRNA analysis. Latrunculin B altered this expression pattern only in stiffer substrates, in which knock on effects on expression of ECM proteins relevant to glaucoma such as CTGF and PAI-1 were also seen. These findings provide intriguing insights into cellular mechanisms mediating sensing and regulation of TM biophysical properties in a way that is relevant to glaucoma. They also provide clues to how novel actin-modulating drugs such as Latrunculin B may affect mechanosensing in the TM and insights into novel drug targets. Tissue-based confirmation of these findings will further establish the importance of mechanisms identified here and their relevance to glaucoma.
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