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Editors Selection IGR 10-4
Basic research: Trabecular meshwork: Cytoskeletal reorganization of TM cells
Comment by Douglas Rhee on:
18184 Influence of actin cytoskeletal integrity on matrix metalloproteinase-2 activation in cultured human trabecular meshwork cells, Sanka K; Maddala R; Epstein DL et al., Investigative Ophthalmology and Visual Science, 2007; 48: 2105-2114
In the trabecular meshwork, the three primary theoretical mechanisms of IOP regulation are turnover of extracellular matrix (ECM) within the juxtacanalicular region, flow in between inner wall Schlemm's canal cells (i.e., the 'paracellular' pathway), and flow through intracellular vacuoles within Schlemm's canal cells (i.e., the 'transcellular' pathway). The relationship, if any, among these different mechanisms is not known.
To explore a potential relationship between actin cytoskeletal alteration, a means to affect paracellular resistance, and matrix metalloproteinases, enzymes that enhance ECM turnover, Sanka et al. (419), incubated cultured trabecular meshwork cells with cytoskeletal disrupting agents, cytochalasin D, latrunculin A, ethacrynic acid, Y-27632 (a rho-kinase inhibitor), and H-7 (a serine/threonine kinase inhibitor), and measured the relative activity and level of MMP-2 (gelatinase A) and MMP-14 (MT1-MMP), respectively. Additionally, they measured the amount of TIMP-1 and TIMP-2, two of the four TIMPs (kinetic inhibitors of MMPs) in the trabecular meshwork. To measure the cytoskeletal disruptive effects of their agents, the investigators examined the morphologic effects using phase microscopy and targeted actin stress fibers organization patterns using immunocytochemistry. Because of their findings with latrunculin A and cytochalasin D, they measured the relative expression of enzymes associated with cytoskeletal organization, p38 MAPK and ERK Kinase.
Latrunculin A and cytochalasin D affect both paracellular and ECM turnover regulatory mechanismsThey confirmed that all of the agents demonstrated morphologic evidence of cytoskeletal re-organization. Both latrunculin A and cytochalasin D increased the levels of mRNA of MMP-14, increased MMP-2 activity, and concurrently decreased the levels of TIMPs-1 and -2. Their findings indicate that cellular shape changes induced by some cytoskeletal disruptive agents shifts the balance of secreted MMPs: TIMPs towards greater MMP activity. This shift would favor increased ECM turnover. These results indicate that latrunculin A and cytochalasin D affect both paracellular and ECM turnover regulatory mechanisms and suggests that the two mechanisms may be linked. Latrunculin A and cytochalasin D affect both paracellular and ECM turnover regulatory mechanisms.
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