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Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1α (HIF-1α)–signaling pathway. Furthermore, experimental myopia selectively induced HIF-1α up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O₂) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1α expression as well as the phosphorylation levels of eIF2α and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2α phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia.

The annual increase in myopia prevalence poses a significant economic and health challenge. Our study investigated the effect of calcitriol role in myopia by inducing the condition in guinea pigs through form deprivation for four weeks. Untargeted metabolomics methods were used to analyze the differences in metabolites in the vitreous body, and the expression of vitamin D receptor (VDR) in the retina was detected. Following form deprivation, the guinea pigs received intraperitoneal injections of calcitriol at different concentrations. We assessed myopia progression using diopter measurements and biometric analysis after four weeks. Results indicated that form deprivation led to a pronounced shift towards myopia, characterized by reduced choroidal and scleral thickness, disorganized collagen fibers, and decreased scleral collagen fiber diameter. Notably, a reduction in calcitriol expression in vitreous body, diminished vitamin D and calcitriol levels in the blood, and decreased VDR protein expression in retinal tissues were observed in myopic guinea pigs. Calcitriol administration effectively slowed myopia progression, preserved choroidal and scleral thickness, and prevented the reduction of scleral collagen fiber diameter. Our findings highlight a significant decrease in calcitriol and VDR expressions in myopic guinea pigs and demonstrate that exogenous calcitriol supplementation can halt myopia development, enhancing choroidal and scleral thickness and scleral collagen fiber diameter.

AimsTo evaluate, using anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM), the uveo-scleral aqueous humour (AH) outflow pathways after ultrasonic circular cyclocoagulation (UCCC).MethodsForty-four patients with refractory glaucoma underwent 4 or 6 s UCCC (group 1, 24 eyes; group 2, 20 eyes). UCCC was successful when the preoperative intraocular pressure (IOP) reduced by one-third. AS-OCT and IVCM were performed at baseline and at month 1 to evaluate the sclera and conjunctiva. The main outcomes were mean intra-scleral hyporeflective spaces area (MIHSA: mm2) at AS-OCT, mean density and area of conjunctival microcysts (MMD: cysts/mm2; MMA: µm2) at IVCM. The relations between MIHSA, MMA and MMD with IOP were analysed.ResultsMean baseline IOP was 26.9±2.8 mm Hg in group 1 and 27.5±4.0 in group 2. Intra-scleral hyporeflective spaces and microcysts were observed in both groups, without significant differences in MIHSA, MMA and MMD. At month 1, UCCC was successful in 63.6% of patients (41.6% in group 1, 80% in group 2), and IOP reduced to 18.8±3.2 (30.1%) and 17.1±2.7 mm Hg (38.7%), respectively (p<0.001). MIHSA showed a twofold and threefold increase in group 1 and 2 (p<0.05), with a significant difference between groups (p<0.05). MMA and MMD increased in both groups (p<0.05), with values higher in group 2 (p<0.05). Significant relations were found between MIHSA and IOP in both groups (p<0.01).ConclusionsUCCC induced anatomical modifications of sclera and conjunctiva, which suggested that the trans-scleral AH outflow enhancement is one of the possible mechanisms exploited by ultrasounds to reduce IOP.

The biomechanical behavior of the sclera determines the level of mechanical insult from intraocular pressure to the axons and tissues of the optic nerve head, as is of interest in glaucoma. In this study, we measure the collagen fiber structure and the strain response, and estimate the material properties of glaucomatous and normal human donor scleras. Twenty-two posterior scleras from normal and diagnosed glaucoma donors were obtained from an eyebank. Optic nerve cross-sections were graded to determine the presence of axon loss. The specimens were subjected to pressure-controlled inflation testing. Full-field displacement maps were measured by digital image correlation (DIC) and spatially differentiated to compute surface strains. Maps of the collagen fiber structure across the posterior sclera of each inflated specimen were obtained using synchrotron wide-angle X-ray scattering (WAXS). Finite element (FE) models of the posterior scleras, incorporating a specimen-specific representation of the collagen structure, were constructed from the DIC-measured geometry. An inverse finite element analysis was developed to estimate the stiffness of the collagen fiber and inter-fiber matrix. The differences between glaucoma and non-glaucoma eyes were small in magnitude. Sectorial variations of degree of fiber alignment and peripapillary scleral strain significantly differed between normal and diagnosed glaucoma specimens. Meridional strains were on average larger in diagnosed glaucoma eyes compared with normal specimens. Non-glaucoma specimens had on average the lowest matrix and fiber stiffness, followed by undamaged glaucoma eyes, and damaged glaucoma eyes but the differences in stiffness were not significant. The observed biomechanical and microstructural changes could be the result of tissue remodeling occuring in glaucoma and are likely to alter the mechanical environment of the optic nerve head and contribute to axonal damage.

These studies aimed to study the mechanisms of glaucomatous peripapillary scleral (PPS) remodeling by investigating IOP-induced changes in fibroblast actin-collagen alignment and nuclear morphology in mouse PPS. Cryosections from the optic nerve heads (ONH) of eyes isolated 1- and 6-weeks after bead-induced IOP elevation were imaged for nuclei, fibrillar actin (FA), and collagen (second harmonic generation, SHG). Two-dimensional nuclear morphology was analyzed using VAMPIRE machine-learning image analysis and FA-collagen alignment was determined by comparing vector fields of FA and SHG images. Nuclear morphology was regionally defined with the internal (pial) PPS (iPPS) containing nuclei with higher aspect ratios than the peripheral PPS (outer PPS, oPPS) and peripheral sclera. FA-collagen alignment was higher in the PPS than in the peripheral sclera (7.1 ± 2.5° versus 10.0 ± 1.4°, p  = 0.05, n  = 6). One and six weeks after BI, there were non-significant nuclear morphologic changes reflecting a transition to a rounder shape in all scleral regions and persistently reduced FA-collagen alignment in the PPS regions. This study therefore concludes that chronic IOP elevation is associated with persistent alterations in FA-collagen alignment that indicate sustained cellular responses to tissue stress.

Long-term use of topical prostaglandins might initiate chronic conjunctival inflammation, leading to poor outcomes of glaucoma surgery. The aim of this study was to evaluate the immunoexpression pattern of HSP70, CTGF, SNAIL, aSMA, cMYB, and HIFa in the conjunctiva, episclera, and deep sclera in patients with glaucoma undergoing deep sclerectomy in order to establish an association between staining intensities and prostaglandin F2 (PGF2) treatment. Double immunofluorescence (HSP70, CTGF, SNAIL, aSMA, cMYB, and HIFa) was performed on conjunctiva, episclera, and deep sclera samples, which were obtained from 23 patients treated with PGF2 and 8 patients without PGF2 treatment. When comparing the ocular tissues of patients regarding treatment with PGF2 analogs, we found a significant increase in the immunoexpression of HSP70 in the conjunctival epithelium of patients treated with PGF2 analogs compared to those without PGF2 treatment. These patients also had an increase in SNAIL immunoexpression and a decrease in aSMA immunoexpression in the deep sclera. There were no significant differences in HIFa, CTGF, or cMYB immunoexpression levels between the two groups. Further research into the regulation of these factors in ocular tissues could lead to the development of potential novel therapeutic approaches in glaucoma management.

Background Myopia presents a noteworthy global health concern, urging exploration of innovative treatments. The role of intraocular pressure (IOP) in regulating the progression of myopia has been controversial. Methods To investigate the impact of reducing IOP to varying extents on myopia progression, three groups receiving distinct IOP-lowering medications (Brinzolamide, Latanoprost, and a combination of Brinzolamide and Latanoprost) were designed in a form-deprived myopic guinea pig model. Additionally, proteomics analyses were conducted to identify differentially expressed proteins in the sclera. Results Based on 24-h and 4-week IOP monitoring, the group receiving both Brinzolamide and Latanoprost exhibited the greatest magnitude of IOP reduction and the most significant inhibition of axial length (AL) growth. Moreover, the administration of IOP-lowering medications increased choroidal thickness and induced alterations in the structure of scleral collagen fibrils. Notably, scleral proteomics revealed remodeling processes associated with key mechanisms, including proteolysis, fibrinolysis, and metal ion binding. Conclusions Our findings highlight that pressure-dependent scleral remodeling contributes to the deceleration of AL elongation. These results underscore the efficacy of IOP reduction in mitigating the progression of myopia, providing a promising alternative strategy for myopia management.

Focusing on the mTOR-HIF-1α signaling pathway, this study investigated the mechanism through which the traditional Chinese medicine compound Mingshi Formula delays the progression of form-deprivation myopia (FDM) in guinea pigs. The guinea pigs were divided into the normal control group (NC), FDM group, Mingshi Formula low-dose group (FDM + Low), medium-dose group (FDM + Medium), high-dose group (FDM + High), and MTOR inhibitor group (FDM + RapaLink-1). The guinea pig model of FDM was established by applying 3D-printed hoods modified by a latex balloon with 60% light transmission for 4 weeks. Refractive error changes were monitored using a refractometer. Axial length was quantitatively analyzed using A-scan ultrasound, choroidal thickness was measured with SD-OCT, and structural changes of the choroid and sclera were observed after hematoxylin-eosin (HE) staining. At the molecular level, the expression levels of the mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), HIF-1α, LDHA, PKM2, MMP2, Collagen I, and α-SMA in the sclera were measured by RT-qPCR and Western blotting. The spatial distribution characteristics of mTOR, p-mTOR, HIF-1α, and Collagen I were verified via immunofluorescence techniques. The results demonstrated that the Mingshi Formula significantly decreased myopic refractive error and axial length ( p  < 0.01), increased choroidal thickness ( p  < 0.05), downregulated the gene and protein expression of mTOR, p-mTOR, HIF-1α, LDHA, PKM2, MMP2, and α-SMA in response to hypoxia, and upregulated the expression of Collagen I compared to the FDM group. We demonstrated that MingShi formula modulates the mTOR/HIF-1α signaling axis to ameliorate scleral hypoxic metabolic homeostasis, regulate Collagen synthesis, inhibit aberrant extracellular matrix remodeling, and ultimately delay myopia progression.

Myopia is the most widespread refractive error caused by an increase in the axial length (AL) of the eyeball, and is also a major risk factor for other blinding eye diseases, seriously endangering human health and quality of life. Investigating practical methods to control the progression of myopia is therefore crucial. The only medication that has been shown to effectively delay the progression of myopia over an extended period of time is atropine. Although they have more adverse effects, atropine eye drops with a high concentration work best to correct myopia. Atropine at low concentrations can slow the progression of myopia, however the results might not be very noticeable. It is of great significance to explore the application of drugs to suppress myopia in combination with low-concentration atropine in the treatment of myopia. This study investigated the role and mechanism of 0.01% atropine combined with carteolol hydrochloride in the treatment of myopia. By establishing a model of form-deprivation myopia in guinea pigs, we examined the protective effect of 0.01% atropine combined with carteolol hydrochloride on myopia in guinea pigs and further explored the mechanism of scleral remodeling mediated by mitochondrial dysfunction. We found that 0.01% atropine combined with carteolol hydrochloride refined mitochondrial dysfunction-induced extracellular matrix degradation by activating the PGC-1α/NRF2/HO-1 signaling pathway, thereby suppressing scleral remodeling and the progression of form-deprivation myopia in guinea pigs. In conclusion, 0.01% atropine combined with carteolol hydrochloride may be an effective strategy for the treatment of myopia.

The present study aimed to investigate the role of the PI3K/Akt signaling pathway in scleral remodeling in the development of negative lens-induced myopia (LIM). The change of scleral morphology in experimental myopic guinea pigs was observed by transmission electron microscopy, Masson staining, and TUNEL assay, respectively. Meanwhile, the levels of the PI3K/AKT signaling pathway- and scleral remodeling-related molecules in scleral tissues were determined by real-time quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemical staining, and western blot, respectively. We found that 2-week myopic induction can elevate PIK3R3 and AKT2 levels and activate the PI3K/Akt signaling pathway, enhance the expression of E-cadherin and matrix metallopeptidase 2 (MMP2), and decrease the level of transforming growth factor-beta 1 (TGF-β1), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and collagen (COLI) in the scleral tissue of myopic guinea pigs, thereby leading to scleral remolding. However, 4-week myopic induction could inhibit the PI3K/AKT signaling pathway and induce apoptosis, accompanied by increased MMP2, E-cadherin, and decreased TGF-β1, TIMP2, and COLI. Results reveal that the disturbed PI3K/AKT signaling plays a role in scleral remodeling in the experimental myopia through orchestrating apoptosis.