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Editors Selection IGR 7-2

Basic Research - Meshwork: Pathogenic role of connective tissue growth factor

Comment by Abbot Clark on:

50293 Connective tissue growth factor causes glaucoma by modifying the actin cytoskeleton of the trabecular meshwork, Junglas B; Kuespert S; Seleem AA et al., American Journal of Pathology, 2012; 180: 2386-2403

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Expression of the profibrotic cytokine TGFβ2 is elevated in the aqueous humor, trabecular meshwork TM and optic nerve head (ONH) of POAG eyes, and TGFβ2 plays a pathogenic role in glaucomatous damage to the TM and ONH. Many of the profibrotic activities of TGFβ2 are mediated by the induction of connective tissue growth factor (CTGF), and CTGF enhances extracellular matrix deposition in the TM and ONH. A very elegant new study by Junglas and colleagues clearly demonstrated that CTGF alone elevates IOP in mice. They generated two mouse models: one using a viral vector to transiently overexpress CTGF in anterior segment tissues, and they also generated a new transgenic mouse line that over-expressed CTGF in the lens, leading to CTGF secretion into the aqueous humor. In both mouse models, increased CTGF expression in anterior segment tissues increased the expression of fibronectin and α-smooth muscle actin in the TM that was associated with elevated IOP. There also was progressive optic nerve axon loss in both models. To identify the molecular mechanism(s) associated with CTGF-induced ocular hypertension, the authors examined the effects of CTGF on cultured TM cells. CTGF enhanced stress fiber formation and cell contractility, which appeared to be due to RhoA activation and increased phosphorylation of MLC, FAK, and ERK1/2. The authors suggest that CTGF effects on the TM actin cytoskeleton are mediating the ocular hypertension. To further explore the role of actin cytoskeleton in this response, they used a ROCK inhibitor to lower ocular hypertension in the CTGF transgenic mice. This study provides new insights into the role of CTGF in glaucoma damage to the TM. In addition, these investigators provide two very important new mouse models that mimic many features of POAG, which be valuable new resources allowing the power of mouse genetics to identify molecular pathogenic pathways in the aqueous outflow pathway as well as glaucomatous optic neuropathy.

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