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Results for “Sclera remodeling”

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At least 19 recordsLinked to original sources

PubMed2005

[Dynamic changes of MMP-2 activity in the posterior sclera of chicks with form-deprivation myopia].

OBJECTIVE: To investigate the effect of form-deprivation on level of gelatinase in the posterior sclera in chicks. METHODS: Fifty 1-day-old chicks were monocularly deprived to establish the animal model of form-deprivation myopia (FDM). According to the duration of form-deprivation the experimental chicks were divided randomly and equivalently into 5 groups, which were deprived for 3, 7, 14, 21 and 30 days respectively. Meanwhile the other eyes of the deprived chicks were used as self-control groups and chicks of the same days were chosen randomly as the normal control groups for each FDM group. At each form-deprivation point the changes of degree of diopters and axial length of chicks in each group were recorded. The levels of gelatinase in posterior sclera of the experimental eyes were measured by gelatin enzymography. RESULTS: Compared with the normal and self-control groups, the levels of MMP-2 activity in FDM groups were much higher (P <0.01). With the increase of the time of monocular deprivation these changes became more significant and reached the top after 14 days' deprivation with an inter-group statistical difference (P <0.01). The dynamic changes of MMP-2 activity were the same as those of axial length and degree of diopters in each experimental groups. There was positive correlation between the MMP-2 activity and axial length (r = 0.989, P < 0.01). But there was a negative correlation between the MMP-2 activity and refractive degree. CONCLUSION: Increase of MMP-2 activity in the posterior sclera of chicks would be a direct key factor to trigger sclera ECM remodeling process in chick FDM.

Animals↗

PubMed2001

Steady state mRNA levels in tree shrew sclera with form-deprivation myopia and during recovery.

PURPOSE: In tree shrews, visual form deprivation induces myopia and tissue remodeling in the sclera, characterized by decreased levels of collagen and glycosaminoglycans (GAGs) and increased levels of matrix metalloproteinases (MMPs). Removal of the visual deprivation allows recovery. This study investigated whether these changes are accompanied by changes in steady state mRNA levels in the sclera. METHODS: Quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to measure steady state levels of mRNA for collagen (alpha1(I) chain), decorin (core protein), gelatinase-A (MMP-2), stromelysin-1 (MMP-3), and a tissue inhibitor of metalloproteinase (TIMP-1) in the scleras of tree shrews that received either 11 days of monocular form deprivation (MD) or 11 days of MD followed by 4 days of recovery. A group of age-matched normal animals was also measured. RESULTS: After 11 days of MD, alpha1(I) collagen mRNA levels were 34% lower, and MMP-2 mRNA levels were 66% higher in the deprived eyes than in the control eyes. After 4 days of recovery, collagen mRNA levels were 33% higher, MMP-2 levels were 20% lower, and TIMP-1 levels were 43% higher in the recovering eyes than in the control eyes. Decorin and MMP-3 mRNA levels were not significantly different between the treated and control eyes after MD or after recovery. CONCLUSIONS: The tissue remodeling in mammalian sclera induced by altering the visual environment is accompanied by modulation of mRNA levels in the sclera. The levels of collagen and MMP-2 mRNA were modulated in a pattern generally consistent with observed changes in protein levels, suggesting that visual regulation of the levels of these scleral proteins may involve modulation of gene expression at the transcriptional level.

Animals↗

PubMed2004

[Matrix metalloproteinase-2 mRNA expression in the posterior sclera of chick form-deprivation myopia].

OBJECTIVE: To investigate the dynamic changes of matrix metalloproteinase-2 (MMP-2) mRNA expression in the posterior sclera of chick form-deprivation myopia (FDM) and its possible molecular mechanism. METHODS: Fifty white 1-day-old leghorn chicks were divided randomly and equally into 5 groups. The right eye of each chick was covered with a plastic goggle at 4, 7, 14, 21, and 30 postborn days respectively to induce FDM, and the left eye served as a self-control. Meanwhile, normal age-matched chicks were provided as negative control speciments for each group. Removing the goggle at every experiment point, refractive status and axial length were determined with streak retinoscopy (without cycloplegia) and A-scan ultra-sonography under topical anaesthesia, respectively. Both eyes were collected after the chicks were killed. The total RNA in the posterior sclera was extracted traditionally using TRIZOL reagent, and then the expression levels of MMP-2 messenger RNA were analyzed by one step reverse transcriptiontase-polymerase chain reaction. RESULTS: Compared with the normal and self-control groups, the expression levels of MMP-2 mRNA in the deprived eyes significantly increased (P < 0.001). With the delay of form-deprivation duration, MMP-2 mRNA expression levels increased significantly and especially reached a highest point at the 14th day of monocular deprivation. After that the level decreased slightly, but maintained at a high level. Although there was no significant difference between the normal control group and the self-control one (P > 0.05), MMP-2 mRNA expressed slightly higher in the self-controlled eyes. CONCLUSION: As a primary element to trigger early active sclera extracellular matrix remodeling process, MMP-2 gene is probably involved in the development of FDM by excessive degradation of extraceller matrix which can make sclera thinner and the eye axis longer.

Animals↗

PubMed1999

Gelatinase A and TIMP-2 expression in the fibrous sclera of myopic and recovering chick eyes.

PURPOSE: Myopia, or nearsightedness, is characterized by excessive lengthening of the ocular globe and is associated with extracellular matrix remodeling in the posterior sclera. The activity of gelatinase A, a member of the matrix metalloproteinase family, has been shown to increase in the posterior sclera during the development of induced myopia in several species. In the present study, the distribution and relative expression of gelatinase A and its associated inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, were measured within the fibrous scleras of experimentally myopic (form-deprived) eyes, control eyes, and eyes recovering from form deprivation to better understand the mechanisms that regulate scleral remodeling and the rate of ocular elongation. METHODS: Total RNA was extracted from the posterior scleras of form-deprived chick eyes, eyes recovering from deprivation myopia, and paired contralateral control eyes, and subjected to northern blot analysis analyses using cDNA probes to chicken gelatinase A and TIMP-2. The distribution of gelatinase A and TIMP-2 mRNAs was evaluated by in situ hybridization on frozen sections of chick scleras using 33P-labeled RNA probes. Gelatinase A activity within the fibrous scleras of form-deprived eyes and paired contralateral recovering eyes was evaluated by gelatin zymography. RESULTS: Northern blot analysis indicated that the relative expression of gelatinase A was increased by 128% in deprived eyes (P = 0.009), whereas after 1 day of recovery, levels were decreased by 80% in scleras from recovering eyes (P = 0.005). In contrast, TIMP-2 expression was significantly decreased (-53%, P = 0.027) in the posterior scleras of form-deprived eyes. No significant differences were detected in levels of TIMP-2 expression between recovering eyes and paired control eyes. In situ hybridization indicated that most of the gelatinase A transcripts were present in the fibrous layer of the posterior scleras from form-deprived and recovering eyes. CONCLUSIONS: Changes in the steady state levels of gelatinase A and TIMP-2 mRNA lead to changes in gelatinase activity within the fibrous sclera and mediate, at least in part, the process of visually regulated ocular growth and scleral remodeling.

Animals↗

PubMed2005

Persistent posterior globe flattening after orbital cavernous haemangioma excision.

A 54-year-old man presented with left intraconal cavernous haemangioma resulting in globe compression and hyperopia. The tumour was excised completely via lateral orbitotomy approach. Complete excision of tumour did not result in resolution of globe flattening and hyperopia after 21 months. Persistent globe flattening despite removal of a longstanding orbital tumour may be caused by remodelling of the sclera from long-term compression.

Choroid Diseases↗

PubMed2006

Characterization of the integrin receptor subunit profile in the mammalian sclera.

PURPOSE: During the increased eye growth that results in myopia, the sclera undergoes biochemical and biomechanical remodeling. The cell surface integrin receptor family has important roles during tissue remodeling, regulating the extracellular matrix environment and cellular biomechanical properties. As integrin receptors may have a role in remodeling during myopia, this study detailed subunit gene expression in the mammalian sclera. METHODS: Several tissues, including sclera, were isolated from the tree shrew, a mammalian model used in eye growth studies. Total RNA was purified, reverse transcribed and primers for the alpha- and beta-integrin subunits were designed to the published human sequence in areas of high inter-species homology. PCR was used to amplify products of predetermined size and all tree shrew integrin subunits were sequenced to confirm their identity. Multiple PCR conditions were used to identify the scleral integrin subunits, and positive control tissues were included to reduce the possibility of false negative results. RESULTS: Integrin PCR products corresponding to the beta1-, beta4-, beta5-, and beta8-integrin subunits and the alpha-integrin subunits, alpha1-6-, alpha9-11- and alphav-integrin were identified in the sclera and in scleral fibroblast cultures. The respective sequences showed a high identity (>81%) to their human counterparts. The beta2-, beta3-, beta6-, beta7-, alpha7-, and alpha8-integrin subunits were not detected in tree shrew scleral samples, despite being present in the respective positive controls. Association of the 4 beta-integrin subunits with the 10 alpha-integrin subunits suggests that the mammalian sclera is capable of expressing 13 of the 24 identified integrin receptors. CONCLUSIONS: This is the first systematic description of the integrin subunit expression profile in the sclera. Due to the multiple roles of integrin receptors during tissue remodeling, the identification of these scleral integrins is an important preliminary step in determining the role of these receptors during normal eye growth and myopia development.

Animals↗

PubMed1994

Visual deprivation upregulates extracellular matrix synthesis by chick scleral chondrocytes.

PURPOSE: To characterize the cellular events responsible for the exaggerated ocular growth associated with experimental myopia in chicks, the accumulation and synthesis of proteoglycans and collagen were measured in the posterior sclera of control and form vision-deprived chick eyes. METHODS: Buttons (10 mm) from the posterior sclera of control and deprived eyes were used for biochemical measurements of glycosaminoglycans and hydroxyproline to estimate proteoglycan and collagen accumulation, respectively. The synthesis of proteoglycan, collagen, total protein, and RNA were measured in cultures of scleral chondrocytes isolated from posterior scleral buttons of control and deprived eyes by measuring the specific incorporation of 35SO4, [3H]proline, [35S]methionine, and [5-3H]uridine, respectively. The relative rate of aggrecan precursor protein synthesis was measured in cultures of control and deprived chondrocytes using immunoprecipitation assays. RESULTS: Form deprivation resulted in increased accumulation of proteoglycans but not collagen within the posterior sclera. In contrast, chondrocytes isolated from the posterior sclera of form-deprived eyes maintained elevated rates compared with controls of proteoglycan synthesis (+143%) and collagen synthesis (155%), as well as total protein synthesis (115%) and total RNA synthesis (44%). Because total protein synthesis was higher in cultures of deprived chondrocytes, the rate of aggrecan precursor protein synthesis, relative to total protein synthesis, was similar for both populations of cells. Pretreatment of scleral chondrocytes with actinomycin D, an inhibitor of RNA synthesis, resulted in a 112% increase in the rate of proteoglycan synthesis by control chondrocytes, but had no significant effect on the rate of proteoglycan synthesis by chondrocytes isolated from form-deprived eyes. CONCLUSIONS: Because proteoglycans accumulate within the posterior sclera of deprived eyes to a greater extent than collagen, yet form deprivation stimulates the synthesis of collagen and total protein as well as proteoglycans, these data suggest that collagen, and perhaps other scleral components, are selectively remodeled within the posterior sclera during the process of ocular elongation. Furthermore, experiments with actinomycin D suggest that the general upregulation observed in form-deprived chondrocytes may be due to the absence of a inhibitor normally present under conditions of form vision.

Animals↗

PubMed1995

Increased latent gelatinase activity in the sclera of visually deprived chicks.

PURPOSE: Gelatinase activity was measured in the normal chick sclera and in sclera of form-deprived (myopic) eyes to assess the role of this metalloproteinase in ocular elongation associated with experimental myopia. METHODS: Gelatinases were extracted from anterior and posterior regions of normal chick sclera and sclera from eyes that had been form-vision deprived for 11 days. Gelatinase activity in the extracts was determined by measuring the digestion of 3H-gelatin after incubation with the extracts in the absence or presence of 1 mM aminophenylmercuric acetate (APMA) to activate latent gelatinases. Scleral gelatinases were characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography and immunoprecipitation analyses. RESULTS: No significant differences were detected in gelatinase activity between normal and deprived posterior sclera in the absence of APMA. However, when scleral extracts were incubated with APMA, extracts from the posterior sclera of deprived eyes contained significantly more gelatinase activity than paired controls (+127%, P = 0.0105). In contrast, no differences in active or latent gelatinase activity were detected in extracts from the anterior sclera. Removal of tissue inhibitors of metalloproteinases (TIMP) from control scleral extracts by reduction and alkylation resulted in a 222% increase in gelatinolytic activity after APMA-activation (P < or = 0.001), whereas similar treatment of deprived scleral extracts resulted in only a 76% increase in gelatinolytic activity (P < or = 0.001). A 65/58-kd doublet was the major gelatinolytic species from control and deprived posterior sclera that represent the proenzyme and active forms of the 72-kd gelatinase (MMP-2). CONCLUSIONS: These data indicate that visual deprivation is associated with an increased amount of the 72-kd progelatinase and a decreased amount of TIMP within the posterior sclera. Therefore, an imbalance between the levels of 72-kd progelatinase and its inhibitor may play a role in the remodeling processes of the posterior sclera during the development of form-deprivation myopia.

Animals↗

PubMed1996

Form-deprivation myopia induces activation of scleral matrix metalloproteinase-2 in tree shrew.

PURPOSE: To investigate whether structural changes to the sclera during form-deprivation myopia are caused by active tissue remodeling, the gelatinase activity of tree shrew scleras was studied in normal animals, form-vision deprived animals, and animals recovering from myopia. METHODS: Infant tree shrews were monocularly deprived (MD) of form vision with translucent occluders for 5 days. Recovery animals were allowed 3 days of binocularly unoccluded vision after the period of form deprivation. Eyes were removed and dissected to provide scleral samples corresponding to equatorial and posterior regions. Gelatinase activity was assessed by quantitative sodium dodecyl sulfate-polyacrylamide gel electrophoresis or SDS-PAGE, gelatin, zymography of scleral matrix metalloproteinase (MMP) extracts. RESULTS: The major gelatinolytic species present in tree shrew sclera was found to be MMP-2 (gelatinase A). In normal (nondeprived) animals, most of the MMP-2 was found to be in the latent form (the ratio of active-to-latent MMP-2 was 0.23 +/- 0.05 and 0.34 +/- 0.06 in equatorial and posterior samples, respectively; n = 10 eyes from five animals). After 5 days of MD, there was a threefold increase in the amount of active scleral MMP-2 in myopic eyes compared to contralateral control eyes, whereas latent MMP-2 activity levels were not altered significantly. This increase in active MMP-2 was seen in both the equatorial and posterior sclera of myopic eyes (active-to-latent MMP-2 ratios were 0.53 +/- 0.10 and 0.81 +/- 0.09 in equatorial and posterior regions, respectively; n = 6 animals). Contralateral control eyes had levels of both active and latent MMP-2 not significantly different from normal eyes. After only 3 days of unoccluded vision, previously deprived eyes that were now recovering from myopia had a fivefold lower level of active MMP-2 than that seen in deprived eyes after 5 days of MD. In fact, active (and latent) MMP-2 levels were reduced in recovering eyes even below the levels found in their contralateral control eyes. Active-to-latent ratios for recovering eyes were 0.11 +/- 0.03 and 0.15 +/- 0.03 in equatorial and posterior sclera, respectively (n = 5 animals). CONCLUSIONS: These results demonstrate that form-deprivation myopia and recovery from myopia alter scleral catabolism and provide further support for the theory that changes in eye size during mammalian refractive development are the result of active tissue remodeling rather than passive scleral stretching alone.

Animals↗

PubMed2000

Decreased proteoglycan synthesis associated with form deprivation myopia in mature primate eyes.

PURPOSE: The rate of proteoglycan synthesis was measured in the scleras of adolescent marmosets that had undergone monocular form deprivation to characterize the scleral extracellular matrix changes associated with the development of myopia in a mature primate. METHODS: Form deprivation myopia was induced in adolescent marmosets by unilateral lid suture for an average of 108 days. After the lids were reopened, the axial lengths and refractions were measured at intervals for up to 39 weeks. At the end of the study period, sclera were isolated and immediately radiolabeled with 35SO4 in organ culture. Proteoglycan synthesis rates were determined by measurement of 35SO4 incorporation into cetylpyridinium chloride-precipitable glycosaminoglycans after digestion of the scleral samples with proteinase K. Collagen content was determined by measurement of total hydroxyproline in scleral digests. Newly synthesized proteoglycans were separated on a Sepharose CL-4B molecular sieve column and identified by their core proteins by Western blot analyses. RESULTS: Lid suture resulted in myopia due to a significant increase in vitreous chamber depth. After Sepharose CL-4B chromatography, newly synthesized scleral proteoglycans isolated from normal, form-deprived, and contralateral control eyes, resolved into one major peak that eluted in the position of decorin, a small chondroitin-dermatan sulfate proteoglycan. After digestion of the major peak with chondroitinase ABC, an approximately 45-kDa core protein was detected by Western blot analyses, confirming the presence of decorin. Form deprivation resulted in a significant reduction in the rate of proteoglycan synthesis in the posterior sclera (-43.55%, P < or = 0.001). Proteoglycan synthesis was also significantly reduced in the posterior sclera of form-deprived eyes relative to total collagen content (-36.19%, P < or = 0.01) and was negatively correlated with the rate of vitreous chamber elongation in the deprived eye (r2 = 0.779, P < or = 0.05). CONCLUSIONS: Significant extracellular matrix remodeling occurs in the posterior sclera of the adolescent primate eye during vitreous chamber elongation and myopia development. The negative correlation between vitreous chamber elongation rates and the synthesis rates of decorin in form-deprived eyes suggests that proteoglycan synthesis within the posterior sclera plays a role in the regulation of ocular size and refraction in the adolescent marmoset.

Animals↗

PubMed2005

Selective regulation of MMP and TIMP mRNA levels in tree shrew sclera during minus lens compensation and recovery.

PURPOSE: In juvenile tree shrews, a minus-power lens placed in front of the eye produces increased axial elongation and a myopic shift in refractive state that compensates for the power of the lens. Scleral tissue remodeling and modulation of the mechanical properties of the sclera occur during lens compensation. In this study, the time course of changes in scleral mRNA levels of three MMPs and three TIMPs during compensation for a minus lens and during recovery was investigated, to determine which, if any, are temporally associated with changes in the mechanical properties of the sclera and the axial elongation rate. METHODS: Competitive RT-PCR was used to measure the levels of mRNA for MT1-MMP, MMP-2, MMP-3, TIMP-1, TIMP-2, and TIMP-3 in the scleras of tree shrews that had received either 1, 2, 4, or 11 days of monocular -5-D lens treatment, or 11 days of -5-D lens treatment followed by 2 or 4 days of recovery. RESULTS: Relative to their control eyes, treated eye MT1-MMP and MMP-2 mRNA levels were significantly higher, and TIMP-3 levels were lower by 1 to 4 days of minus lens treatment. These differential effects were absent by 11 days of treatment when the treated eyes had compensated for the lens. The levels of all three TIMPs spiked upward in both eyes after 2 days of recovery. The differential changes in MT1-MMP, MMP-2, and TIMP-3 mRNA levels were all restricted to the treated eye and were temporally associated with the differential changes in axial elongation, refractive state, and the previously measured changes in creep rate. CONCLUSIONS: The observed changes in MT1-MMP, MMP-2, TIMP-2, and TIMP-3 mRNA are consistent with visually modulated MT1-MMP activation of MMP-2 and with MT1-MMP degradation of scleral extracellular matrix components. These data constitute further evidence that visual signals modulate gene expression of selected MMPs and TIMPs to control scleral remodeling, the mechanical properties of the sclera, axial elongation, and refractive state.

Animals↗

PubMed2000

Scleral remodeling during the development of and recovery from axial myopia in the tree shrew.

PURPOSE: Recent investigations have suggested that scleral thinning in mammalian eyes with axial myopia is a consequence of the loss of scleral tissue, rather than the redistribution of existing tissue as the eye enlarges. The present study investigated whether further changes in the distribution and metabolism of scleral tissue occur during the process of recovery from axial myopia. Scleral glycosaminoglycan (GAG) synthesis and content as well as scleral dry weight changes were monitored as indicators of remodeling in myopic and recovering tree shrew sclerae. METHODS: Myopia was induced in tree shrews by monocularly depriving them of pattern vision. Some animals then had the occluder removed and were allowed to recover from the induced myopia for periods of 1, 3, 5, 7, and 9 days. Newly synthesized GAGs were radiolabeled in vivo with [(35)S]sulfate. Sulfate incorporation and total GAG content in the sclera was measured through selective precipitation of GAGs from proteinase K digests with alcian blue dye. Dry weights of the sclerae were also determined. Changes in ocular refraction and eye size were monitored using retinoscopy, keratometry, and ultrasonography. RESULTS: Eyes developing myopia showed a significant reduction in scleral GAG synthesis, particularly in the region of the posterior pole (-36% +/- 7%) compared with contralateral control eyes. Scleral dry weight was also significantly reduced in these eyes (-3.7% +/- 1.2%). In recovering eyes, significant changes in GAG synthesis were apparent after 24 hours of recovery. After 3 days of recovery, significantly elevated levels of GAG synthesis were found (+79% +/- 15%), returning to contralateral control eye values after 9 days of recovery. Interocular differences in scleral dry weight were shown to follow a similar pattern to that observed for GAG synthesis. CONCLUSIONS: Active remodeling, resulting in either the loss or replacement of scleral tissue and not passive redistribution of scleral tissue, is associated with changes in eye size during both myopia development and recovery. Regulatory changes in scleral metabolism can be rapidly evoked by a change in visual conditions and the direction of regulation is related to the direction of change in eye size.

Animals↗

PubMed2025

Intraocular pressure is a promising target for myopia control.

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.

Myopia↗

PubMed2026

Increased PRSS56 expression is a causal factor and therapeutic target for human axial high myopia.

High myopia (HM), characterized by significant ocular axial length elongation, affects hundreds of millions of people and is often inherited, particularly in cases that develop during childhood or adolescence. Although numerous myopia loci (MYP) have been identified, most causative genes remain undefined. Here, we analyzed two large HM pedigrees and refined the critical region through haplotype linkage analysis to a 3.9-Mb interval on 2q37.1, which was previously reported as MYP12 with an unknown pathogenic gene. Whole-genome sequencing identified the noncoding promoter variants c.-187G>T and c.-187G>C in PRSS56, encoding a trypsin-like serine protease, which exclusively co-segregated with all affected members in both pedigrees. Compared with matched controls, increased PRSS56 expression was observed in both patient-derived iPSCs carrying c.-187G>T and knock-in mice (c.-155G>T, corresponding to human c.-187G>T) that faithfully recapitulate myopia phenotypes. Noncoding PRSS56 variants promote self-expression via enhanced binding to the transcription factor EGR1, as confirmed by dual-luciferase assays. Notably, we demonstrated that higher PRSS56 levels directly increase ocular axial length in a dose- and activity-dependent manner in multiple transgenic mouse models. Guinea pig myopia models consistently exhibited high Prss56 expression, and short-wave light exposure reduced Prss56 mRNA levels and attenuated further axial elongation. Mechanistically, higher PRSS56 expression was associated with reduced abundance of myosin-4 in the sclera and with molecular signatures of scleral remodeling, which were in turn correlated with axial elongation. In conclusion, our findings provide strong genetic and functional evidence for the pathogenic role of noncoding PRSS56 variants in HM and highlight PRSS56 as a promising therapeutic target for juvenile HM.

Humans↗

PubMed2006

Expression of collagen-binding integrin receptors in the mammalian sclera and their regulation during the development of myopia.

PURPOSE: The sclera has a collagen-rich extracellular matrix that undergoes significant biochemical and biomechanical remodeling during myopic eye growth. The integrin family of cell surface receptors play critical roles in extracellular matrix and biomechanical remodeling in connective tissues. This study identified the major collagen-binding integrin receptors in the mammalian sclera and investigated their mRNA expression during the development of and recovery from experimental myopia. METHODS: The presence of the alpha1, alpha2, and beta1 integrin subunits was examined by using tree-shrew-specific primers and RT-PCR. Scleral expression of alpha1beta1 and alpha2beta1 receptor proteins was further investigated by using Western blot analysis and immunocytochemistry. Myopia was induced monocularly by occluding pattern vision and scleral tissue collected after 24 hours and 5 days. In a subset of the 5-day treatment group, vision was restored for 24 hours before tissue was isolated. Total RNA was extracted, and integrin subunit expression levels were assessed with quantitative real-time PCR. RESULTS: The presence of the major collagen-binding integrin subunits alpha1, alpha2, and beta1 was confirmed by RT-PCR in both scleral tissue and cultured scleral fibroblasts. Both the alpha1 and alpha2 integrin subunit proteins were identified in tree shrew scleral tissues, and integrin receptor expression was localized to scleral fibroblast focal adhesions. After only 24 hours of myopia induction, a time when no structural elongation has occurred, significant decreases were observed in the expression of the alpha1 (-36%) and beta1 (-44%) integrin subunits. After 5 days of myopia induction, alpha1 integrin expression had returned to baseline levels, whereas the alpha2 subunit showed a significant decrease in expression (-52%). The 5-day integrin profiles were maintained during recovery from the induced myopia, with only alpha2 integrin showing a statistically significant relative decrease in expression (-41%). CONCLUSIONS: The mammalian sclera expresses the major collagen-binding integrin subunits. The alpha1 and beta1 subunit expression was decreased early during the development of myopia, whereas the regulation of alpha2 integrin occurred at a later time point. The differential regulation of alpha1beta1 and alpha2beta1 during the development of myopia may reflect specific roles for these receptors in the scleral extracellular matrix and biomechanical remodeling that accompanies myopic eye growth.

Animals↗

PubMed2000

Scar remodeling after strabismus surgery.

PURPOSE: We sought to investigate abnormal scar lengthening after strabismus surgery. METHODS: Patients with overcorrection after strabismus surgery or undercorrection after extraocular muscle resection underwent exploration of previously operated muscles. Abnormal findings were documented by inspection and photography, and repair was undertaken at first with absorbable sutures and later with nonabsorbable sutures. RESULTS: Lengthened scars, consisting of amorphous connective tissue, were repaired on 198 muscles in 134 procedures by excision of the scar and reattachment of the muscle to sclera; absorbable sutures were used in 64 procedures, and nonabsorbable sutures were used in 70 procedures. Thirty-one procedures were followed by partial recurrence of the original overcorrection; 7 of these had documented restretching. The use of nonabsorbable sutures decreased the recurrence of strabismus from 42% to 6%. Factors that distinguished patients with stretched scars from patients with classic slipped muscles included minimal or no limitation of versions, less separation of the tendons from sclera, and thicker appearance of the scar segments. CONCLUSIONS: A lengthened or stretched remodeled scar between an operated muscle tendon and sclera may contribute to variability of outcome after strabismus repair, even years later. Definitive repair requires firm reattachment of tendon to sclera with nonabsorbable suture support.

Adolescent↗

PubMed2002

Role of adrenergic receptors in vascular remodelling of the rat choroid.

1. Choroidal blood vessels, located between the sclera and retina, constitute the principle source of blood flow to ocular structures. The choroid is innervated by vasoconstrictor sympathetic and vasodilator parasympathetic nerves. 2. We have shown previously that sympathetic denervation for 6 weeks leads to significant increases in choroidal thickness, percentage of choroid occupied by vascular lumina, and numbers of choroidal venules, large arterioles and outer retinal capillaries. Sympathetic deafferentation produces similar increases, indicating that loss of sympathetic nerve activity is responsible for increased vascularity after sympathectomy. Thus, sympathetic neurotransmission normally may be important in suppressing vascular proliferation in the adult rodent eye. 3. The aim of the present study was to determine whether sympathetic nerves act by way of adrenergic receptors to maintain normal choroidal vascular integrity. 4. The alpha-adrenoceptor antagonist, phentolamine (1 mg kg(-1) day(-1)), the beta-receptor antagonist, propranolol (1 mg kg(-1) day(-1)), or saline vehicle was infused for 3 weeks using subcutaneously implanted osmotic minipumps. 5. In phentolamine treated rats, no significant changes were noted relative to saline infused controls. However, propranolol treatment resulted in increases in choroidal thickness, vascular luminal area, and numbers of large choroidal venules and both small and large arterioles, approximating the remodelling seen after chronic sympathectomy. 6. We conclude that sympathetic nerves play a role in maintaining normal choroidal vascular architecture through actions mediated primarily by beta-adrenoceptors.

Adrenergic Antagonists↗

PubMed2005

Neonatal aphakia retards ocular growth and alters scleral gene expression in rhesus monkeys.

PURPOSE: We hypothesize that remodeling of the scleral extracellular matrix, involving collagen and proteoglycan synthesis and turnover, is a key process involved in ocular growth. Decreased axial elongation is observed following neonatal removal of the crystalline lens in a rhesus monkey model of congenital cataract. We wanted to determine changes in gene expression in the operated and companion eye following lensectomy, especially for extracellular matrix in the sclera. METHODS: Between 4 and 7 days of age, infant monkeys underwent surgical removal of the lens from the right eye. Axial lengths of the operated and unmanipulated fellow eyes were measured and when interocular differences of >0.4 mm were achieved, monkeys were sacrificed and RNA was isolated from sclera. In order to determine changes in scleral gene expression in aphakic versus control eyes, we used Clontech's Atlas Gene Array (Human Cancer Array version 1.2) hybridized with total RNA from three monkeys. RESULTS: Atlas Gene Array analysis demonstrated differential expression of several genes in the operated versus the unmanipulated eye. Most notably, there was a statistically significant increase in expression of several extracellular matrix (ECM) genes including: aggrecan, decorin, biglycan, several collagens, and tenascin in the RNA from the sclera of the aphakic eyes when compared to the unmanipulated eyes. Genes for several matrix metalloproteinases (MMPs) showed no significant change following lens removal although there was a trend towards decreased expression. There were also statistically significant changes in the pattern of gene expression in the operated eye relative to the unmanipulated eye for cell adhesion, cell cycle, apoptosis, and cytoskeleton transcripts. CONCLUSIONS: Our results suggest that removal of the crystalline lens alters gene expression in the sclera with a prominent upregulation of ECM transcripts. These data support recent evidence that remodeling of the ECM composition of the sclera may be an important regulator of ocular growth.

Animals↗