Research

14 pages, 1815 KiB

Open AccessArticle

Changes in Expression in BMP2 and Two Closely Related Genes in Guinea Pig Retinal Pigment Epithelium during Induction and Recovery from Myopia

by So Goto, Yan Zhang, Sonal Aswin Vyas, Qiurong Zhu and Christine F. Wildsoet

Biomolecules 2023, 13(9), 1373; https://doi.org/10.3390/biom13091373 - 11 Sep 2023

Viewed by 1007

Abstract

Purpose: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain [...] Read more.

Purpose: We previously reported differential gene expression of the bone morphogenetic protein 2 (Bmp2) in guinea pig retinal pigment epithelium (RPE) after 1 day of hyperopic defocus, imposed with a negative contact lens (CLs). The study reported here sought to obtain insights into the temporal profiles of gene expression changes in Bmp2, as well as those of two closely related genes, the inhibitor of DNA binding 3 (Id3) and Noggin (Nog), both during myopia induction and when the CL treatment was terminated to allow recovery from induced myopia. Methods: To induce myopia, 2-week-old pigmented guinea pigs (New Zealand strain, n = 8) wore monocular −10 diopter (D) rigid gas-permeable (RGP) CLs for one week, while the other eye served as a control. Ocular measurements were made at baseline, 3 days, and 7 days after the initiation of CL wear, with treatment then being terminated and additional measurements being made after a further 3 days, 1 week, and 2 weeks. Spherical equivalent refractive errors (SERs), axial length (AL), choroidal thickness (ChT), and scleral thickness (ScT) data were collected using retinoscopy, optical biometry (Lenstar), and spectral domain optical coherence tomography (SD-OCT), respectively. RPE samples were collected from both eyes of the guinea pigs after either 1 day or 1 week of CL wear or 1 day or 2 weeks after its termination, and RNA was subsequently isolated and subjected to quantitative real-time PCR (qRT-PCR) analyses, targeting the Bmp2, Id3, and Nog genes. Results: Mean interocular differences (treated—control) in AL and SER were significantly different from baseline after 3 and 7 days of CL wear, consistent with induced myopia (p < 0.001 for all cases). Termination of CL wear resulted in the normalization (i.e., recovery) of the ALs and SERs of the treated eyes within 7 days, and the earlier significant ChT thinning with CL wear (p = 0004, day 7) was replaced by rapid thickening, which remained significant on day 7 (p = 0.009) but had normalized by day 14. The ChT changes were much smaller in magnitude than the AL changes in both phases. Interocular differences in the ScT showed no significant changes. The Bmp2 and Id3 genes were both significantly downregulated with CL wear, after 1 day (p = 0.012 and 0.016) and 7 days (p = 0.002 and 0.005), while Bmp2 gene expression increased and Nog gene expression decreased after the termination of CL wear, albeit transiently, which was significant on 1 day (p = 0.004 and 0.04) but not 2 weeks later. No change in Id3 gene expression was observed over the latter period. Conclusions: The above patterns of myopia induction and recovery validate this negative RGP-CL model as an alternative to traditional spectacle lens models for guinea pigs. The defocus-driven, sign-dependent changes in the expression of the Bmp2 gene in guinea pig RPE are consistent with observations in chicks and demonstrate the important role of BMP2 in eye growth regulation. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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17 pages, 1919 KiB

Open AccessArticle

Biomarker Signature in Aqueous Humor Mirrors Lens Epithelial Cell Activation: New Biomolecular Aspects from Cataractogenic Myopia

by Maria De Piano, Andrea Cacciamani, Bijorn Omar Balzamino, Fabio Scarinci, Pamela Cosimi, Concetta Cafiero, Guido Ripandelli and Alessandra Micera

Biomolecules 2023, 13(9), 1328; https://doi.org/10.3390/biom13091328 - 29 Aug 2023

Cited by 1 | Viewed by 947

Abstract

Inflammatory, vasculogenic, and profibrogenic factors have been previously reported in vitreous (VH) and aqueous (AH) humors in myopic patients who underwent cataract surgery. In light of this, we selected some mediators for AH and anterior-capsule-bearing lens epithelial cell (AC/LEC) analysis, and AH expression [...] Read more.

Inflammatory, vasculogenic, and profibrogenic factors have been previously reported in vitreous (VH) and aqueous (AH) humors in myopic patients who underwent cataract surgery. In light of this, we selected some mediators for AH and anterior-capsule-bearing lens epithelial cell (AC/LEC) analysis, and AH expression was correlated with LEC activation (epithelial–mesenchymal transition and EMT differentiation) and axial length (AL) elongation. In this study, AH (97; 41M/56F) and AC/LEC samples (78; 35M/43F) were collected from 102 patients who underwent surgery, and biosamples were grouped according to AL elongation. Biomolecular analyses were carried out for AH and LECs, while microscopical analyses were restricted to whole flattened AC/LECs. The results showed increased levels of interleukin (IL)-6, IL-8, and angiopoietin-2 (ANG)-2 and decreased levels of vascular endothelium growth factor (VEGF)-A were detected in AH depending on AL elongation. LECs showed EMT differentiation as confirmed by the expression of smooth muscle actin (α-SMA) and transforming growth factor (TGF)-βR1/TGFβ isoforms. A differential expression of IL-6R/IL-6, IL-8R/IL-8, and VEGF-R1/VEGF was observed in the LECs, and this expression correlated with AL elongation. The higher VEGF-A and lower VEGF-D transcript expressions were detected in highly myopic LECs, while no significant changes were monitored for VEGF-R transcripts. In conclusion, these findings provide a strong link between the AH protein signature and the EMT phenotype. Furthermore, the low VEGF-A/ANG-2 and the high VEGF-A/VEGF-D ratios in myopic AH might suggest a specific inflammatory and profibrogenic pattern in high myopia. The highly myopic AH profile might be a potential candidate for rating anterior chamber inflammation and predicting retinal distress at the time of cataract surgery. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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26 pages, 4994 KiB

Open AccessFeature PaperArticle

Molecular Basis of Transglutaminase-2 and Muscarinic Cholinergic Receptors in Experimental Myopia: A Target for Myopia Treatment

by Veluchamy Amutha Barathi, Candice E. H. Ho and Louis Tong

Biomolecules 2023, 13(7), 1045; https://doi.org/10.3390/biom13071045 - 27 Jun 2023

Viewed by 1282

Abstract

Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined [...] Read more.

Myopia, a prevalent refractive error disorder worldwide, is characterized by the elongation of the eye, leading to visual abnormalities. Understanding the genetic factors involved in myopia is crucial for developing therapeutic and preventive measures. Unfortunately, only a limited number of genes with well-defined functionality have been associated with myopia. In this study, we found that the homozygous TGM2-deleted gene in mice protected against the development of myopia by slowing down the elongation of the eye. The effectiveness of gene knockdown was confirmed by achieving a 60 percent reduction in TGM-2 transcript levels through the use of TGM-2-specific small interfering RNA (siRNA) in human scleral fibroblasts (SFs). Furthermore, treating normal mouse SFs with various transglutaminase inhibitors led to the down-regulation of TGM-2 expression, with the most significant reduction observed with specific TGM-2 inhibitors. Additionally, the study found that the pharmacological blockade of muscarinic receptors also slowed the progression of myopia in mice, and this effect was accompanied by a decrease in TGM-2 enzyme expression. Specifically, mice with homozygous mAChR5, mAChR1, and/or mAChR4 and knockout mice exhibited higher levels of TGM-2 mRNA compared to mice with homozygous mAChR2 and three knockout mice (fold changes of 5.8, 2.9, 2.4, −2.2, and −4.7, respectively; p < 0.05). These findings strongly suggest that both TGM-2 and muscarinic receptors play central roles in the development of myopia, and blocking these factors could potentially be useful in interfering with the progression of this condition. In conclusion, targeting TGM-2 may have a beneficial effect regarding myopia, and this may also be at least partially be the mechanism of anti-muscarinic drugs in myopia. Further studies should investigate the interaction between TGM-2 and muscarinic receptors, as well as the changes in other extracellular matrix genes associated with growth during the development of myopia. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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18 pages, 4858 KiB

Open AccessArticle

Intravitreal Neuroglobin Mitigates Primate Experimental Glaucomatous Structural Damage in Association with Reduced Optic Nerve Microglial and Complement 3-Astrocyte Activation

by Anita S. Y. Chan, Sai B. B. Tun, Myoe N. Lynn, Candice Ho, Tin A. Tun, Michaël J. A. Girard, Rehena Sultana, Veluchamy A. Barathi, Tin Aung and Makoto Aihara

Biomolecules 2023, 13(6), 961; https://doi.org/10.3390/biom13060961 - 08 Jun 2023

Viewed by 1579

Abstract

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We [...] Read more.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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19 pages, 3652 KiB

Open AccessArticle

GABA_B Receptor Activation Affects Eye Growth in Chickens with Visually Induced Refractive Errors

by Hong Liu, Frank Schaeffel, Zhikuan Yang and Marita Pauline Feldkaemper

Biomolecules 2023, 13(3), 434; https://doi.org/10.3390/biom13030434 - 24 Feb 2023

Viewed by 1426

Abstract

This study aims to explore the role of GABA_B receptors in the development of deprivation myopia (DM), lens-induced myopia (LIM) and lens-induced hyperopia (LIH). Chicks were intravitreally injected with 25 µg baclofen (GABA_BR agonist) in one eye and saline into [...] Read more.

This study aims to explore the role of GABA_B receptors in the development of deprivation myopia (DM), lens-induced myopia (LIM) and lens-induced hyperopia (LIH). Chicks were intravitreally injected with 25 µg baclofen (GABA_BR agonist) in one eye and saline into the fellow eye. Choroidal thickness (ChT) was measured via OCT before and 2, 4, 6, 8, 24 h after injection. ChT decreased strongly at 6 and 8 h after baclofen injection and returned back to baseline level after 24 h. Moreover, chicks were monocularly treated with translucent diffusers, −7D or +7D lenses and randomly assigned to baclofen or saline treatment. DM chicks were injected daily into both eyes, while LIM and LIH chicks were monocularly injected into the lens-wearing eyes, for 4 days. Refractive error, axial length and ChT were measured before and after treatment. Dopamine and its metabolites were analyzed via HPLC. Baclofen significantly reduced the myopic shift and eye growth in DM and LIM eyes. However, it did not change ChT compared to respective saline-injected eyes. On the other hand, baclofen inhibited the hyperopic shift and choroidal thickening in LIH eyes. All the baclofen-injected eyes showed significantly lower vitreal DOPAC content. Since GABA is an inhibitory ubiquitous neurotransmitter, interfering with its signaling affects spatial retinal processing and therefore refractive error development with both diffusers and lenses. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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18 pages, 3298 KiB

Open AccessEditor’s ChoiceArticle

Fibrotic Response of Human Trabecular Meshwork Cells to Transforming Growth Factor-Beta 3 and Autotaxin in Aqueous Humor

by Mengxuan Liu, Megumi Honjo, Reiko Yamagishi, Nozomi Igarashi, Natsuko Nakamura, Makoto Kurano, Yutaka Yatomi, Koji Igarashi and Makoto Aihara

Biomolecules 2022, 12(9), 1231; https://doi.org/10.3390/biom12091231 - 03 Sep 2022

Cited by 4 | Viewed by 1703

Abstract

This study examines the potential role of transforming growth factor-beta 3 (TGF-β3) on the fibrotic response of cultured human trabecular meshwork (HTM) cells. The relationships and trans-signaling interactions between TGF-β3 and autotaxin (ATX) in HTM cells were also examined. The levels of TGF-β [...] Read more.

This study examines the potential role of transforming growth factor-beta 3 (TGF-β3) on the fibrotic response of cultured human trabecular meshwork (HTM) cells. The relationships and trans-signaling interactions between TGF-β3 and autotaxin (ATX) in HTM cells were also examined. The levels of TGF-β and ATX in the aqueous humor (AH) of patients were measured by an immunoenzymetric assay. The TGF-β3-induced expression of the fibrogenic markers, fibronectin, collagen type I alpha 1 chain, and alpha-smooth muscle actin, and ATX were examined by quantitative real-time PCR, Western blotting, and immunocytochemistry, and the trans-signaling regulatory effect of TGF-β3 on ATX expression was also evaluated. In HTM cells, the significant upregulation of ATX was induced by TGF-β3 at a concentration of 0.1 ng/mL, corresponding to the physiological concentration in the AH of patients with exfoliative glaucoma (XFG). However, higher concentrations of TGF-β3 significantly suppressed ATX expression. TGF-β3 regulated ATX transcription and signaling in HTM cells, inducing the upregulation of fibrogenic proteins in a dose-dependent manner. Trans-signaling of TGF-β3 regulated ATX transcription, protein expression, and signaling, and was thereby suggested to induce fibrosis of the trabecular meshwork. Modulation of trans-signaling between TGF-β3 and ATX may be key to elucidate the pathology of XFG, and for the development of novel treatment modalities. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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Review

Jump to: Research, Other

18 pages, 697 KiB

Open AccessReview

Applications of Genomics and Transcriptomics in Precision Medicine for Myopia Control or Prevention

by Liqin Jiang, Dong Xuan Goh, James Hao Zhong Koh, Xavier Chan, Noel A. Brennan, Veluchamy Amutha Barathi and Quan V. Hoang

Biomolecules 2023, 13(3), 494; https://doi.org/10.3390/biom13030494 - 07 Mar 2023

Cited by 5 | Viewed by 1892

Abstract

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for [...] Read more.

Myopia is a globally emerging concern accompanied by multiple medical and socio-economic burdens with no well-established causal treatment to control thus far. The study of the genomics and transcriptomics of myopia treatment is crucial to delineate disease pathways and provide valuable insights for the design of precise and effective therapeutics. A strong understanding of altered biochemical pathways and underlying pathogenesis leading to myopia may facilitate early diagnosis and treatment of myopia, ultimately leading to the development of more effective preventive and therapeutic measures. In this review, we summarize current data about the genomics and transcriptomics of myopia in human and animal models. We also discuss the potential applicability of these findings to precision medicine for myopia treatment. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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Other

Jump to: Research, Review

11 pages, 3708 KiB

Open AccessOpinion

Glaucoma and Myopia: Diagnostic Challenges

by Michelle T. Sun, Matthew Tran, Kuldev Singh, Robert Chang, Huaizhou Wang and Yang Sun

Biomolecules 2023, 13(3), 562; https://doi.org/10.3390/biom13030562 - 20 Mar 2023

Cited by 2 | Viewed by 4919

Abstract

The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among [...] Read more.

The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among patients with normal intraocular pressures. These patients may also present with established visual field defects which can mimic glaucoma, and standard imaging technology is less useful in disease detection and monitoring due to the lack of normative data for these anatomically unique eyes. Progression over time remains the most critical factor in facilitating the detection of early glaucomatous changes, and thus careful longitudinal follow-up of high-risk myopic patients is the most important aspect of management. Here, we review our current understanding of the complex relationship between myopia and glaucoma, and the diagnostic challenges and limitations of current testing protocols including visual field, intraocular pressure, and imaging. Furthermore, we discuss the clinical findings of two highly myopic patients with suspected glaucoma. Full article

(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)

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