The role of lamina cribrosa tissue stiffness and fibrosis as fundamental biomechanical drivers of pathological glaucoma cupping
The primary biomechanical driver of pathological glaucomatous cupping remains unknown. Finite element modeling indicates that stress and strain play key roles. In this article, primarily a review, we utilize known biomechanical data and currently unpublished results from our lab to propose a three-stage, tissue stiffness-based model to explain glaucomatous cupping occurring at variable levels of translaminar pressure (TLP). In stage 1, a short-term increase in TLP gradient induces a transient increase in lamina cribrosa (LC) strain. Beyond a critical level of strain, the tissue stiffness rises steeply provoking cellular responses via integrin-mediated mechanotransduction. This early mechanoprotective cellular contraction reduces strain, which reduces tissue stiffness by return of the posteriorly deflected LC to baseline. In stage 2 a prolonged period of TLP increase elicits extracellular matrix (ECM) production leading to fibrosis, increasing baseline tissue stiffness and strain and diminishing the contractile ability/ability to return to the baseline LC position. This is supported by our three-dimensional collagen contraction assays, which show significantly reduced capacity to contract in glaucoma compared with normal LC cells. Second, 15% cyclic strain in LC cells over 24 h elicits a typical increase in ECM profibrotic genes in normal LC cells but a highly blunted response in glaucoma LC cells. Stage 3 is characterized by persistent fibrosis causing further stiffening and inducing a feed-forward ECM production cycle. Repeated cycles of increased strain and stiffness with profibrotic ECM deposition prevent optic nerve head (ONH) recoil from the new deflected position. This incremental maladaptive modeling leads to pathological ONH cupping.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:319 |
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| Enthalten in: |
American journal of physiology. Cell physiology - 319(2020), 4 vom: 01. Okt., Seite C611-C623 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hopkins, Alan A [VerfasserIn] |
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| Links: |
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| Themen: |
Glaucoma |
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| Anmerkungen: |
Date Completed 17.12.2020 Date Revised 17.12.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1152/ajpcell.00054.2020 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312443196 |
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| 245 | 1 | 4 | |a The role of lamina cribrosa tissue stiffness and fibrosis as fundamental biomechanical drivers of pathological glaucoma cupping |
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| 500 | |a Date Revised 17.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The primary biomechanical driver of pathological glaucomatous cupping remains unknown. Finite element modeling indicates that stress and strain play key roles. In this article, primarily a review, we utilize known biomechanical data and currently unpublished results from our lab to propose a three-stage, tissue stiffness-based model to explain glaucomatous cupping occurring at variable levels of translaminar pressure (TLP). In stage 1, a short-term increase in TLP gradient induces a transient increase in lamina cribrosa (LC) strain. Beyond a critical level of strain, the tissue stiffness rises steeply provoking cellular responses via integrin-mediated mechanotransduction. This early mechanoprotective cellular contraction reduces strain, which reduces tissue stiffness by return of the posteriorly deflected LC to baseline. In stage 2 a prolonged period of TLP increase elicits extracellular matrix (ECM) production leading to fibrosis, increasing baseline tissue stiffness and strain and diminishing the contractile ability/ability to return to the baseline LC position. This is supported by our three-dimensional collagen contraction assays, which show significantly reduced capacity to contract in glaucoma compared with normal LC cells. Second, 15% cyclic strain in LC cells over 24 h elicits a typical increase in ECM profibrotic genes in normal LC cells but a highly blunted response in glaucoma LC cells. Stage 3 is characterized by persistent fibrosis causing further stiffening and inducing a feed-forward ECM production cycle. Repeated cycles of increased strain and stiffness with profibrotic ECM deposition prevent optic nerve head (ONH) recoil from the new deflected position. This incremental maladaptive modeling leads to pathological ONH cupping | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a tissue stiffness | |
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| 700 | 1 | |a Irnaten, Mustapha |e verfasserin |4 aut | |
| 700 | 1 | |a Wallace, Deborah M |e verfasserin |4 aut | |
| 700 | 1 | |a Quill, Barry |e verfasserin |4 aut | |
| 700 | 1 | |a O'Brien, Colm |e verfasserin |4 aut | |
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