Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix

Raghunathan, Vijay Krishna; Morgan, Joshua T.; Park, Shin Ae; Weber, Darren; Phinney, Brett S.; Murphy, Christopher J.; Russell, Paul

doi:10.1167/iovs.15-16739

Cited by 144 publications

(151 citation statements)

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“…We also found that inhibition of the Wnt signaling pathway by DKK1 increased IOP [43]. One potential mechanism for this increase is through the stiffening of the trabecular meshwork [45,46]. Also, inhibition of the canonical Wnt signaling may promote ECM deposition [47].…”

Section: Discussionmentioning

confidence: 99%

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A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

et al. 2017

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The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain. Based on maximum IOP change in the perfused eye, the BTM cell strain was identified as a DEX-responder or non-responder strain. Three responder and three non-responder BTM cell strains were cultured, treated with 0.1% ethanol or 100nM DEX for 7 days. RNA and proteins were extracted for RNA sequencing (RNAseq), qPCR, and Western immunoblotting (WB), respectively. Data were analyzed using the human and bovine genome databases as well as Tophat2 software. Genes were grouped and compared using Student’s t-test. We found that DEX induced fibronectin expression in responder BTM cells but not in non-responder cells using WB. RNAseq showed between 93 and 606 differentially expressed genes in different expression groups between responder and non-responder BTM cells. The data generated by RNAseq were validated using qPCR. Pathway analyses showed 35 pathways associated with differentially expressed genes. These genes and pathways may play important roles in GC-induced OHT and will help us to better understand differential ocular responsiveness to GCs.

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Section: Discussionmentioning

confidence: 99%

“…In human osteoblasts, Ohnaka and colleagues found that DKK1 is up-regulated by GCs [48,49]. DKK1 is also increased in the extracellular matrix of DEX treated TM cells [45]. Therefore, DKK1 and the associated Wnt signaling, may play important roles in ocular GC responsiveness.…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

et al. 2017

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“…Using atomic force microscopy, it was demonstrated that trabecular meshwork tissue in POAG eyes is stiffer than in normal human eyes (Last et al, 2011; Russell and Johnson, 2012). Relevant to SIOH, it was shown that treatment of normal human eyes with glucocorticoids in vitro resulted in a 2-fold increase in trabecular meshwork cell stiffness, and the matrix deposited by these cells was approximately 4-fold stiffer (Raghunathan et al, 2015). Similarly, topical glucocorticoid treatment in live rabbits resulted in a 3.5-fold increase in trabecular meshwork stiffness.…”

Section: Biomechanicsmentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

125

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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“…DEX also increases β3 integrin via the Nuclear factor of activated T-cells 1c (NFAT1c) transcription factor (Faralli et al, 2013). DEX treatment induces a 2-fold and ~ 4-fold increase in HTM and rabbit TM cell stiffness and elevates the expression of matrix proteins (decorin, myocilin, and fibrillin, secreted frizzle-related protein (SFRP1) (Raghunathan et al, 2015), and increases protein levels of ZO-1 and Cx43 in both NTM and GTM cells (Zhuo et al, 2010). Tektas and Lutjen-Drecoll, 2009 have shown differences between POAG and steroid-induced glaucomatous TM tissues.…”

Section: Mechanism Of Steroid-induced Secondary Ocular Hypertensionmentioning

confidence: 99%

Glucocorticoid therapy and ocular hypertension

Dibas

Yorio

2016

European Journal of Pharmacology

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The projected number of people who will develop age-related macular degeneration in estimated at 2020 is 196 million and is expected to reach 288 million in 2040. Also, the number of people with Diabetic retinopathy will grow from 126.6 million in 2010 to 191.0 million by 2030. In addition, it is estimated that there are 2.3 million people suffering from uveitis worldwide. Because of the anti-inflammatory properties of glucocorticoids (GCs), they are often used topically and/or intravitreally to treat ocular inflammation conditions or edema associated with macular degeneration and diabetic retinopathy. Unfortunately, ocular GC therapy can lead to severe side effects. Serious and sometimes irreversible eye damage can occur as a result of the development of GC-induced ocular hypertension causing secondary open-angle glaucoma. According to the world health organization, glaucoma is the second leading cause of blindness in the world and it is estimated that 80 million will suffer from glaucoma by 2020. In the current review, mechanisms of GC-induced damage in ocular tissue, GC-resistance, and enhancing GC therapy will be discussed.

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Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix

Cited by 144 publications

References 88 publications

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Glucocorticoid therapy and ocular hypertension

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