The Effects of Glaucoma on the Pressure-Induced Strain Response of the Human Lamina Cribrosa

Midgett, Dan; Liu, Baiyun; Ling, Yik Tung Tracy; Jefferys, Joan L.; Quigley, Harry A.; Nguyen, Thao D.

doi:10.1167/iovs.61.4.41

Cited by 29 publications

(19 citation statements)

References 60 publications

(90 reference statements)

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“…Our findings clearly support that astrocytes can sense mechanical cues in their ambient substratum and react on biomechanical alterations of the surrounding environment with changes in GFAP, vimentin and CCN2/CTGF synthesis. Additionally, the increased CCN2/CTGF levels in the periphery of the glaucomatous human ON, but not the central part supports the finding that the lamina cribrosa strains were larger in the peripheral lamina cribrosa compared to the central lamina cribrosa, and lamina cribrosa strains in the more severely damage glaucoma group were larger than those in the more mildly damaged group and larger differences were measured between peripheral and central lamina cribrosa strains in the more severely damaged glaucoma group ( Midgett et al, 2020 ). The increased lamina cribrosa strain can be sensed by ON cells, like astrocytes and/or lamina cribrosa cells.…”

Section: Discussionsupporting

confidence: 66%

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Dillinger

Weber

Mayer

et al. 2022

Front. Cell Dev. Biol.

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In primary open-angle glaucoma (POAG), a neurodegenerative disease of the optic nerve (ON) and leading cause of blindness, the optic nerve head (ONH) undergoes marked structural extracellular matrix (ECM) changes, which contribute to its permanent deformation and to degeneration of ON axons. The remodeling process of the ECM causes changes in the biomechanical properties of the ONH and the peripapillary sclera, which is accompanied by an increased reactivity of the resident astrocytes. The molecular factors involved in the remodeling process belong to the Transforming growth factor (TGF)-β superfamily, especially TGF-β2. In previous publications we showed that TGF-β2 induced ECM alterations are mediated by Cellular Communication Network Factor (CCN)2/Connective Tissue Growth Factor (CTGF) and recently we showed that CCN2/CTGF is expressed by astrocytes of the ON under normal conditions. In this study we wanted to get a better understanding of the function of CCN2/CTGF under normal and pathologic conditions. To this end, we analyzed the glial lamina and peripapillary sclera of CCN2/CTGF overexpressing mice and studied the effect of CCN2/CTGF and increasing substratum stiffness on murine ON astrocytes in vitro. We observed enhanced astrocyte reactivity in the ONH, increased ECM protein synthesis in the peripapillary sclera and increased Ccn2/Ctgf expression in the ONH during the pathologic development in situ. CCN2/CTGF treatment of primary murine ON astrocytes induced a higher migration rate, and increase of ECM proteins including fibronectin, elastin and collagen type III. Furthermore, the astrocytes responded to stiffer substratum with increased glial fibrillary acidic protein, vimentin, actin and CCN2/CTGF synthesis. Finally, we observed the reinforced appearance of CCN2/CTGF in the lamina cribrosa of glaucomatous patients. We conclude that reactive changes in ONH astrocytes, induced by the altered biomechanical characteristics of the region, give rise to a self-amplifying process that includes increased TGF-β2/CCN2/CTGF signaling and leads to the synthesis of ECM molecules and cytoskeleton proteins, a process that in turn augments the stiffness at the ONH. Such a scenario may finally result in a vicious circle in the pathogenesis of POAG. The transgenic CTGF-overexpressing mouse model might be an optimal model to study the chronic pathological POAG changes in the ONH.

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Section: Discussionsupporting

confidence: 66%

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Dillinger

Weber

Mayer

et al. 2022

Front. Cell Dev. Biol.

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“…39,40 It is suggested by FEA that adduction-induced mechanical strain on the lamina cribrosa could markedly exceed the strain created by an IOP of 45 mmHg, which has been observed to be small both in vivo 41 and ex vivo. 42 Simulation also suggests that the peripapillary and lamina cribrosa strain created by adduction tethering is exaggerated when the ON is stiffer (Park and Demer, unpublished data 2020). Thus, adduction-induced mechanical strain might play a causative role in the development of ON atrophy.…”

Section: Discussionmentioning

confidence: 99%

Adduction-Induced Strain on the Optic Nerve in Primary Open Angle Glaucoma at Normal Intraocular Pressure

Clark

Suh

Giaconi

et al. 2020

Current Eye Research

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Purpose/Aim: The optic nerve (ON) becomes taut during adduction beyond ~26° in healthy people and patients with primary open angle glaucoma (POAG), but only retracts the globe in POAG. We used magnetic resonance imaging (MRI) to investigate this difference. Materials and Methods: MRI was obtained in 2-mm quasi-coronal planes in central gaze, and smaller (~23-25°) and larger (~30-31°) adduction and abduction in 21 controls and 12 POAG subjects whose intraocular pressure never exceeded 21 mmHg. ON cross-sections were analyzed from the globe to 10 mm posteriorly. Area centroids were used to calculate ON path lengths and changes in cross-sections to calculate elongation assuming volume conservation. Results: For both groups, ON path was nearly straight (<102.5% of minimum path) in smaller adduction, with minimal further straightening in larger adduction. ON length was redundant in abduction, exceeding 103% of minimum path for both groups. For normals, the ON elongated 0.4 ± 0.5 mm from central gaze to smaller adduction, and 0.4 ± 0.5 mm further from smaller to larger adduction. For POAG subjects, the ON did not elongate on average from central gaze to smaller adduction and only 0.2 ± 0.4 mm from smaller to larger adduction (P = .045 vs normals). Both groups demonstrated minimal ON elongation not exceeding 0.25 mm from central gaze to smaller and larger abduction. The globe retracted significantly more during large adduction in POAG subjects than normals (0.6 ± 0.7 mm vs 0.2 ± 0.5 mm, P = .027), without appreciable retraction in abduction. For each mm increase in globe axial length, ON elongation in large adduction similarly increased by 0.2 mm in each group. Conclusions:The normal ON stretches to absorb force and avert globe retraction in adduction. In POAG with mild to severe visual field loss, the relatively inelastic ON tethers and retracts the globe during adduction beyond ~26°, transfering stress to the optic disc that could contribute to progressive neuropathy during repeated eye movements.

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“…Early reorganization that can be studied in monkey glaucoma models has identified an immediate, hypercompliant mechanical response to IOP elevation [ 21 – 23 ]. This is followed later by an increase in overall and regional stiffness in monkey [ 24 ], human [ 25 , 26 ], and mouse [ 27 ] eyes. It has not been established what cellular or extracellular events underlie these two phases of ONH response.…”

Section: Introductionmentioning

confidence: 99%

Astrocyte responses to experimental glaucoma in mouse optic nerve head

et al. 2020

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Purpose To delineate responses of optic nerve head astrocytes to sustained intraocular pressure (IOP) elevation in mice. Methods We elevated IOP for 1 day to 6 weeks by intracameral microbead injection in 4 strains of mice. Astrocyte alterations were studied by transmission electron microscopy (TEM) including immunogold molecular localization, and by laser scanning microscopy (LSM) with immunofluorescence for integrin β1, α-dystroglycan, and glial fibrillary acidic protein (GFAP). Astrocyte proliferation and apoptosis were quantified by Ki67 and TUNEL labeling, respectively. Results Astrocytes in normal optic nerve head expressed integrin β1 and α-dystroglycan by LSM and TEM immunogold labeling at electron dense junctional complexes that were found only on cell membrane zones bordering their basement membranes (BM) at the peripapillary sclera (PPS) and optic nerve head capillaries. At 1–3 days after IOP elevation, abnormal extracellular spaces appeared between astrocytes near PPS, and axonal vesical and mitochondrial accumulation indicated axonal transport blockade. By 1 week, abnormal spaces increased, new collagen formation occurred, and astrocytes separated from their BM, leaving cell membrane fragments. Electron dense junctional complexes separated or were absent at the BM. Astrocyte proliferation was modest during the first week, while only occasional apoptotic astrocytes were observed by TEM and TUNEL. Conclusions Astrocytes normally exhibit junctions with their BM which are disrupted by extended IOP elevation. Responses include reorientation of cell processes, new collagen formation, and cell proliferation.

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The Effects of Glaucoma on the Pressure-Induced Strain Response of the Human Lamina Cribrosa

Abstract: The effects of glaucoma on the pressure-induced strain response of the human lamina cribrosa. Invest

Cited by 29 publications

References 60 publications

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Adduction-Induced Strain on the Optic Nerve in Primary Open Angle Glaucoma at Normal Intraocular Pressure

Astrocyte responses to experimental glaucoma in mouse optic nerve head

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