Glaucomatous cupping of the lamina cribrosa: A review of the evidence for active progressive remodeling as a mechanism

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Abstract

The purpose of this review is to examine the literature in an attempt to elucidate a biomechanical basis for glaucomatous cupping. In particular, this work focuses on the role of biomechanics in driving connective tissue remodeling in the progression of laminar morphology from a normal state to that of an excavated glaucomatous state. While there are multiple contributing factors to the pathogenesis of glaucoma, we focus on laminar extracellular matrix (ECM) remodeling in glaucoma and the feedback mechanisms and signals that may guide progressive laminar cupping. We review the literature on the potential mechanisms of glaucomatous changes in the laminar ECM at the anatomic, structural, cellular and subcellular levels in the context of the biomechanical paradigm of glaucomatous onset and progression. Several conclusions can be drawn from this review. First, extensive remodeling of the lamina cribrosa ECM occurs in primary open angle glaucoma. Second, there is surprisingly little evidence to support acute mechanical damage to the lamina as the principal mechanism of cupping. Third, ONH astrocytes and lamina cribrosa cells can sense their mechanical environment and respond to mechanical stimuli by remodeling the ECM. Fourth, there is evidence suggesting that chronic remodeling of the lamina results in a progressive posterior migration of the laminar insertion into the canal wall, which eventually results in the posterior lamina inserting into the pia mater. Finally, modeling studies suggest that laminar remodeling may be a biomechanical feedback mechanism through which cells modify their environment in an attempt to return to a homeostatic mechanical environment. It is plausible that biomechanics-driven connective tissue remodeling is a mechanism in the progression of laminar morphology from a normal state to that of a cupped, excavated glaucomatous state.

Section snippets

Introduction and scope

Lowering intraocular pressure (IOP) remains the only proven method of preventing the onset and progression of glaucoma. The role of IOP in the disease, however, remains controversial. This largely arises from the wide spectrum of individual susceptibility to IOP wherein a significant number of patients with normal IOPs develop glaucoma (e.g. normotensive glaucoma), and other individuals with elevated IOP show no signs of the disease. It is therefore important to understand the relationship

A biomechanical perspective of glaucoma

It is generally accepted that the laminar region of the ONH is the principal site of RGC axonal insult in glaucoma, and therefore a natural site of interest when studying glaucoma (Quigley, 2005). In addition, the region is also interesting from a biomechanical perspective because it is a discontinuity in the corneo-scleral shell. Such discontinuities are often considered weak spots in mechanically loaded systems as they can sometimes be the site of substantial stress concentrations.

The

Laminar connective tissue remodeling

Roberts and coworkers have shown that in a monkey model of early experimental glaucoma, the volume of the laminar connective tissues is approximately 80% larger in glaucoma eyes compared to their contralateral controls (Roberts et al., 2009), but that the relative proportion of connective to neural tissue within the laminar region changed minimally. This study also showed that the early glaucoma eyes had an average of 27% more horizontally oriented laminar beams through the thickness of the

Mechanotransduction in the lamina cribrosa

Several studies have investigated the mechanisms of cell mechanotransduction in astrocyte and LC cells in vitro (O’Brien et al., 1997, Kirwan et al., 2004, Kirwan et al., 2005, Rogers et al., 2010). Kirwan et al. (2004) have shown that cyclical mechanical stretch of the substrate on which cells were grown induced significant increases in TGF-β1 mRNA synthesis after 12 h and TGF-β1 protein secretion after 24 h. Both applied cyclical stretch and exogenously delivered TGF-β1 significantly increased

Modeling of laminar biomechanics

Numerical modeling has therefore become a common approach to study ONH biomechanics and evaluate hypothetical scenarios (Edwards and Good, 2001, Sigal et al., 2005, Sigal et al., 2009a, Sigal et al., 2009b, Sander et al., 2006, Downs et al., 2009, Grytz and Meschke, 2009, Sigal, 2009, Roberts et al., 2010, Roberts et al., in press). Fig. 6 shows an example of the predictions made with a finite element model of the ONH. Although the magnitude and distribution of the strains depends on the

Conclusion

When viewed in the context of ONH biomechanics and the glaucomatous changes in the laminar ECM at the anatomic, structural, cellular and subcellular levels, it seems plausible that connective tissue remodeling is a mechanism in the progression of laminar morphology from a normal state to that of a cupped, excavated glaucomatous state (Fig. 7). This remodeling is adaptive, at least for the load-bearing connective tissue, although it may not prevent irreparable harm to the retinal ganglion cells.

Acknowledgements

This work was supported by USPHS grants R01-EY18926 (JCD) and R01-EY19333 (JCD) from the National Eye Institute, Bethesda, Maryland.

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