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Editors Selection IGR 8-2
Basic Science: Scleral properties may impact glaucoma damage
Comment by Ernst Tamm on:
59292 Experimental scleral cross-linking increases glaucoma damage in a mouse model, Kimball EC; Nguyen C; Steinhart MR et al., Experimental Eye Research, 2014; 128: 129-140
Intraocular pressure acts as a mechanical load that produces stress and strain to the glial and connective tissues in region of the optic nerve head. There is evidence that both human glaucoma and animal models of glaucoma lead to an increased scleral stiffness. The goal of the study was to determine whether scleral stiffening as observed in human glaucoma is a beneficial adaptation or rather a detrimental contributor to optic nerve injury. To follow up on this very critical question, Kimball and colleagues designed a clever experimental approach. Offbred CD1 mice were treated with three subconjunctival injections of 0.5 M glyceraldehyde (GA) in one week, a treatment that is known to increase the stiffness of the mouse sclera by collagen crosslinking. Next, high intraocular pressure glaucoma was induced by bead injection into the anterior chamber. GA treatment did not cause obvious structural or functional defects, but lead to a steeper pressure-strain behavior of the sclera indicating increased stiffness. Most intriguingly, GA-treated eyes had greater retinal ganglion cell (RGC) axon loss from elevated intraocular pressure than either buffer-injected or control eyes. Clearly, this appears to be the first report that experimental alteration of the sclera, by cross-linking, increases susceptibility to RGC damage in mice. The important next step will be to identify the cellular and molecular mechanisms that are behind scleral stiffening in human glaucoma, and TGF-β signaling appears to be a likely candidate. A very likely cause for the higher activity of TGF-β signaling that was observed in the optic nerve heads of human patients with glaucoma is the intraocular pressure-induced strain in the optic nerve head extracellular matrix. Transmission of cell force via integrins is known to be one major mechanism to activate latent TGF-β from extracellular matrix stores.
TGF-β signaling might be the common mechanism that causes both aqueous humor outflow and optic nerve head changes in glaucoma, an unifying concept that might open new and novel causative pathways for therapy
Mechanical activation of latent TGF-β is more efficient with higher cell forces and extracellular matrix stiffening. Quite intriguingly, there is substantial evidence that higher activity of TGF-β signaling and of its downstream mediator connective tissue growth factor is the causative factor behind the increased stiffness of trabecular meshwork and Schlemm's canal endothelium that is observed in human glaucoma and is thought to be a causative factor for the increase in outflow resistance. TGF-β signaling might be the common mechanism that causes both aqueous humor outflow and optic nerve head changes in glaucoma, an unifying concept that might open new and novel causative pathways for therapy.
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