Reduced Scleral TIMP-2 Expression Is Associated With Myopia Development: TIMP-2 Supplementation Stabilizes Scleral Biomarkers of Myopia and Limits Myopia Development

Liu, Hsin‐Hua; Kenning, Megan S.; Jobling, Andrew I; McBrien, Neville A.; Gentle, Alex

doi:10.1167/iovs.16-21181

Cited by 43 publications

(29 citation statements)

References 43 publications

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“…Fink [41] proposed that more studies should be performed to elucidate the existence of the oxygenase which can use methane as a substrate, the methane receptor in cell, and the relationship between methanol, reactive alcohol, NAD(P)+/NAD(P)H ratio, and methane. More studies are required to confirm the effect of MS on microglial activation before it can be used in clinical practice [42]. We hypothesize that methane might have the effect of regulating the classical (M1) and alternative (M2) balance of microglia and promoting microglia M1 conversion to M2 in SCI.…”

Section: Discussionmentioning

confidence: 99%

Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

Wang

Huang

et al. 2017

Oxidative Medicine and Cellular Longevity

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Objective. We investigated the hypothesis that methane-rich saline (MS) can be used to repair spinal cord injury (SCI) in a rat model through suppressing microglial activation related to oxidative, inflammatory, and apoptotic injury. Methods. MS was injected intraperitoneally in rats after SCI. Hematoxylin-eosin (HE) staining, oxidative stress, inflammatory parameters, and cell apoptosis were detected 72 h after SCI to determine the optimal dose. Then, we investigated the protective mechanisms and the long-term effects of MS on SCI. HE and microglial activation were observed. Neurological function was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale. Results. MS can significantly decrease infarct area and inhibit oxidative stress, inflammation, and cell apoptosis 72 h following SCI. The MS protective effect at a dose of 20 ml/kg was better. Moreover, MS can significantly suppress microglial activation related to oxidative and inflammatory injury after SCI and improve hind limb neurological function. Conclusion. MS could repair SCI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis produced by activated microglia. MS provides a novel and promising strategy for the treatment of SCI.

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Section: Discussionmentioning

confidence: 99%

Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

Wang

Huang

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…MMP2 is one of the most important MMPs during the myopia process. The production of MMP2 was demonstrated to increase in animal models of myopia, enhancing the degradation of the scleral ECM components such as COL1 ( Liu et al, 2017 ; Zhao et al, 2018 ). Concordantly, biomechanical tests of the myopic models showed an increased creep rate and elasticity of the sclera ( Phillips et al, 2000 ; McBrien et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…Concordantly, biomechanical tests of the myopic models showed an increased creep rate and elasticity of the sclera ( Phillips et al, 2000 ; McBrien et al, 2009 ). Interfering with the expression of MMP2 could slow down myopia development in animal models ( Liu et al, 2017 ; Zhao et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The Dynamic Scleral Extracellular Matrix Alterations in Chronic Ocular Hypertension Model of Rats

et al. 2020

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Intraocular pressure (IOP) generates stress and strains in the laminar cribrosa and sclera, which may affect the development and progression of glaucoma. Scleral stiffness and material components have changed under elevated IOP. However, the detailed changes of the components of the hypertensive sclera are not well understood. In this study, we aimed to investigate the changes of the main components in the scleral extracellular matrix (ECM), and matrix metalloproteinase 2 (MMP2) and their relationship with time under chronic elevated IOP in Sprague-Dawley rats. An ocular hypertension model was established in the right eyes by anterior chamber injection with 0.3% carbomer solution. The left eye was used as the contralateral control. Immunofluorescent imaging of the tissue frozen sections, Western blot analysis, and quantitative PCR (qPCR) were performed to detect the expressions of type I collagen (COL1), elastin, and MMP2 in the sclera. The ocular hypertension model was successfully established. As compared to the left eyes, the immunofluorescence imaging, Western blot analysis, and qPCR showed that COL1, elastin, and MMP2 were significantly increased in the right eyes at 1 week (all P < 0.05). At 2 weeks, COL1 in the right eyes tended to be lower than that in the left eyes, while elastin and MMP2 were still higher (all P < 0.05) in the right eyes. When the IOP was elevated for 4 weeks, both COL1 and MMP2 were lower than those in the left eyes (all P < 0.05), while elastin between the two eyes was similar (P > 0.05). Under this 4-week hypertensive state, COL1 and elastin were initially elevated at 1 week, and then obviously reduced from 2 to 4 weeks. Consistently, MMP2 was gradually increased, with a peak at 2 weeks, and then decreased at 4 weeks. In conclusion, the chronic elevated IOP induced dynamic scleral ECM alterations in rats in a pressure-and time-dependent manner. MMP2 may play an important role in the balance between ECM synthesis and degradation and could potentially be a novel target for glaucoma intervention.

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“…30,31 Another factor that affects the ECM remodeling process is the balance between the levels of MMPs and their natural endogenous inhibitors, that is, tissue inhibitors of matrix metalloproteinases. 21,22,24,32 The role of changes in tissue inhibitors of matrix metalloproteinase-2 expression in ECM remodeling is species specific because this inhibitor suppressed the activities of scleral MMPs and collagen degradation as well as myopia development in tree shrews, 33 whereas it failed to inhibit myopia development in chicks. 34 Even though MMP-2 involvement in myopia has been extensively characterized, heretofore genetically modified animals have not been used to determine whether there is a cause-and-effect relationship between MMP-2 upregulation and myopia in mice.…”

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confidence: 99%

Cause and Effect Relationship between Changes in Scleral Matrix Metallopeptidase-2 Expression and Myopia Development in Mice

Zhao

Zhou

Reinach

et al. 2018

The American Journal of Pathology

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Myopia is a serious sight-compromising condition in which decreases in scleral biomechanical strength are associated with protease up-regulation resulting in thinning of its collagenous framework and changes in the extracellular matrix composition. Matrix metallopeptidase (MMP)-2 is one of the known proteases mediating these alterations. To determine whether MMP-2 up-regulation precedes myopia development, the direct effects of gain and loss in Mmp2 gene function were evaluated on refractive development and form deprivation myopia in mice. Four weeks after injecting an adeno-associated virus serotype 8 packaged Mmp2 overexpression vector (AAV8-Mmp2), scleral MMP-2 up-regulation was accompanied by significant myopia in a normal visual environment. In contrast, AAV8 packaging with shRNA targeting Mmp2 inhibited rises in MMP-2 expression induced by form deprivation by 54% and reduced myopia development by 23% compared with eyes injected with an irrelevant scrambled sequence. Because opposing changes in MMP-2 protein expression levels had corresponding effects on myopia progression, up-regulation of this protease contributes to inducing this condition. This notion of a cause-and-effect relationship between MMP-2 up-regulation and myopia development is supported by showing that form-deprived myopia development was attenuated by 27% in fibroblast-specific Mmp2 deletion (S100a4Mmp2) mice relative to Cre-negative littermates (Mmp2). Therefore, MMP-2 is a potential drug target for inhibiting myopia progression.

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Reduced Scleral TIMP-2 Expression Is Associated With Myopia Development: TIMP-2 Supplementation Stabilizes Scleral Biomarkers of Myopia and Limits Myopia Development

Cited by 43 publications

References 43 publications

Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

The Dynamic Scleral Extracellular Matrix Alterations in Chronic Ocular Hypertension Model of Rats

Cause and Effect Relationship between Changes in Scleral Matrix Metallopeptidase-2 Expression and Myopia Development in Mice

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