Connective Tissue Remodeling in Myopia and its Potential Role in Increasing Risk of Glaucoma

Abstract

Myopia and glaucoma are both increasing in prevalence and are linked by an unknown mechanism as many epidemiologic studies have identified moderate to high myopia as an independent risk factor for glaucoma. Myopia and glaucoma are both chronic conditions that lead to connective tissue remodeling within the sclera and optic nerve head. The mechanobiology underlying connective tissue remodeling differs substantially between both diseases, with different homeostatic control mechanisms. In this article, we discuss similarities and differences between connective tissue remodeling in myopia and glaucoma; selected multi-scale mechanisms that are thought to underlie connective tissue remodeling in both conditions; how asymmetric remodeling of the optic nerve head may predispose a myopic eye for pathological remodeling and glaucoma; and how neural tissue deformations may accumulate throughout both pathologies and increase the risk for mechanical insult of retinal ganglion cell axons.

Keywords: glaucoma; mechanobiology; myopia; ocular biomechanics; optic nerve head; remodeling.

Figure 1:

Multi-scale mechanisms of scleral remodeling in myopia. The green boxes represent structural and material alterations due to remodeling; the blue box represents the primary stimulus; and the orange box represents stimulus detection and signaling pathways. Scleral remodeling during eye development is driven by visual cues and a homeostatic control mechanism that matches the eye’s axial length to its focal length at the organ-scale. Visual cues are detected by the retina, which sends signals through the choroid to the sclera to alter the scleral remodeling rate. Scleral remodeling in myopia leads to axial elongation at the organ-scale, scleral thinning, increased creep rate and cyclic softening at the tissue-scale. We propose that scleral remodeling involves lamellar sliding at the lamellae-scale, and fibril sliding and adaptation of the collagen fibril crimp at the fiber-scale. The colors at the lamellae-scale indicate the local fiber orientation, whereas the intensity is proportional to the collagen fiber density.

Figure 2:

Time-dependent changes in scleral biomechanics during experimentally induced myopia using a −5D lens in tree shrews. Plotted are the differences between lens treated and control eyes, showing a similar time-dependent trend for all of the study variables. The axial elongation rate (red curve, [20]) increases rapidly after lens placement, followed by a decline to normal levels as the eye adapted its axial length to the new focal length. The creep rate (green curve:, [20]) and the collagen fiber crimp angle (blue curve, [13]) show a similar time-dependent trend compared to the axial elongation rate. Based on the model assumptions, the computationally predicted remodeling rate (magenta curve, [22]) predicts an immediate increase in the remodeling rate after lens placement, followed by a gradual decrease that is consistent with the time-dependent biomechanical changes seen in the other curves.

Figure 3:

Multi-scale mechanisms of ONH remodeling in glaucoma. The green boxes represent structural and material alterations due to ONH remodeling; the blue box represents the primary stimulus; and orange boxes represent mechanisms related to RGC axonal injury. The eye is subjected to IOP load at the organ-scale and chronic IOP elevation is the main risk factor for glaucoma. Pathologic ONH remodeling in glaucoma includes changes in scleral stiffness, LC bowing, initial LC thickening, and septa recruitment at the tissue-scale [31, 32, 33, 34, 35, 36]; and the synthesis of new LC beams at the fiber-scale [37]. We propose that these remodeling mechanisms are driven by a mechanical homeostatic control mechanism in an effort to maintain a homeostatic strain condition at the fiber-scale by altering collagen turnover in the ONH connective tissue. Pathologic ONH remodeling is thought to impair axonal transport by a direct or indirect mechanical insult to the RGC axons that pass through the LC porous microstructure. Fiber scale image is modified from a study by Brazile et al. [38]. ONH, optic nerve head; LC, lamina cribrosa; RGC, retinal ganglion cell; IOP, intraocular pressure.

Figure 4:

Schematic illustration of mechanical implications of remodeling of LC beam collagen. (A) Example LC section of a sheep eye fixed at 5 mmHg and the close-up showing the crimped collagen fibers in a single beam. (B) Without remodeling, all LC beams have the same mechanical properties, that is, thin and thick beams have the same tortuosity (top). Thin and thick beams stiffen at the same level of stretch, with the thick beam consistently carrying more force than the thin beam. After remodeling, the thin beam has a lower tortuosity than the thick beam (bottom). The thin beam stiffens at a lower level of stretch. Hence, for this beam, there is a range of stretches within the thin beam carries more force than the thick beam. This also results in the existence of a crossover point at which both beams carry the same force (i.e., the homeostatic strain condition). At a higher level of stretch, the thick beam carries more force than the thin beam. LC, lamina cribrosa.

Figure 5:

Possible interactions at multiple scales between scleral and ONH remodeling in myopia, aging, and glaucoma. At the organ-scale, visual cues drive scleral remodeling that leads to axial elongation and myopia whereas IOP is thought to be the primary load that drives glaucomatous ONH remodeling in adults. At the tissue-scale, the vision-guided remodeling leads to asymmetric morphological changes of the ONH due to differential remodeling in the nasal/temporal sides. The LC and sclera thin as the LC shifts nasally with respect to the Bruch’s membrane opening (BMO). The blue and red ellipses represent en face views of the anterior laminar insertion and BMO, respectively, illustrating the increase in canal area, development of an elliptical canal shape, and relative deformations between the LC and BMO. These relative deformations lead to the tilted and rotated appearance of the myopic ONH, and potentially contribute to the development of peripapillary atrophy. Both, the sclera and the LC stiffen with age [46, 47]. In glaucoma, pathological ONH remodeling involves an initial thickening of the LC and posterior bowing of LC and sclera. ONH remodeling in myopia, age-dependent scleral stiffening, and pathologic remodeling in glaucoma, are all thought to promote glaucomatous LC bowing and tissue deformations in the prelaminar tissues. These prelaminar tissue deformations may accumulate as the eye develops myopia during childhood, ages, and develops glaucoma later in life. At the fiber-scale, the scleral collagen fiber crimp is temporarily increased during myopia development followed by a decrease with age. The age-dependent decrease in crimp angle θ₀, is partially responsible for the increased scleral stiffness with age [45]. Experimental evidence supports the notion that mechanical homeostatic conditions are defined at the fiber-scale. ONH, optic nerve head; IOP, intraocular pressure; LC, lamina cribrosa.