Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells

Honjo, Megumi; Igarashi, Nozomi; Nishida, Junko; Kurano, Makoto; Yatomi, Yutaka; Igarashi, Koji; Kano, Kuniyuki; Aoki, Junken; Aihara, Makoto

doi:10.1167/iovs.17-22807

Cited by 40 publications

(48 citation statements)

References 63 publications

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“…1B). In a previous study, we reported that ATX was upregulated in the AH as well as in the outflow pathway in SOAG patients and that it may be involved in the inflammatory changes in TM that cause elevated IOP 28 . Several previous studies have also shown that cytoskeletal changes induced by ECM deposition and fibrosis of HTM cells impair AH outflow through the TM, leading to IOP elevation.…”

Section: Discussionmentioning

confidence: 94%

“…Measurement of AtX, AtX isoforms, and tGf-β1, 2 and 3 in the AH. The level of ATX in the AH was determined using a two-site immunoenzymatic assay with an ATX assay reagent equipped with a Tosoh AIA system (Tosoh, Tokyo, Japan) as described previously 27,28,54,55 . The TGF-β levels in the AH were measured using the Bio-Plex Pro TGF-β Assay (Bio-Rad, CA, USA) following the manufacturer's protocol.…”

Section: Discussionmentioning

confidence: 99%

“…To improve the prognosis of CMV-positive PSS patients, it is necessary to first understand the mechanisms underlying elevated IOP. Recently, we reported that autotaxin (ATX), a generating enzyme for lysophosphatidic acid (LPA), has a significant impact on IOP in different glaucoma subtypes and fibrotic changes in the TM, especially in secondary glaucoma 27,28 . Thus, in the present study, we explored whether the level of aqueous ATX is altered in CMV-positive PSS patients, and whether ATX or TGF-β are related to elevated IOP.…”

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confidence: 99%

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Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

Igarashi

Honjo

Yamagishi

et al. 2020

Sci Rep

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to examine whether autotaxin (AtX) in the aqueous humor causes elevated intraocular pressure (iop) in patients with posner-Schlossman syndrome (pSS). AtX and transforming growth factor beta (tGf-β) in the aqueous humor were quantified in PSS patients. The expression of ATX and TGF-β in cytomegalovirus (cMV)-infected-human trabecular meshwork (htM) cells was examined. Biological changes in htM cells and monkey Schlemm's canal endothelial (Sce) cells cultured in the conditioned medium of cMV-infected htM cells were analyzed. the expression of AtX and tGf-β1 was upregulated in the aqueous humor of cMV-positive pSS patients, and the level of AtX in the aqueous humor was positively correlated with iop. cMV infection upregulated AtX and tGf-β1 in hTM cells. The conditioned medium induced fibrotic changes in hTM cells and reduced SCE permeability, which was attenuated by an AtX inhibitor, a lysophosphatidic acid receptor antagonist, and a Rho kinase inhibitor. AtX in the aqueous humor induced by cMV infection may trigger elevated iop. Modulating AtX activity may be a novel treatment modality for pSS.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

Igarashi

Honjo

Yamagishi

et al. 2020

Sci Rep

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“…However, Dex treatment did not decrease ATX activity significantly in liver and kidney, which indicates that there is organspecific regulation. In fact, Dex was reported to increase ATX expression in human trabecular meshwork cells and to be associated with fibrotic changes in the eye (55).…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

et al. 2018

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Lysophosphatidate (LPA) signaling through 6 receptors is regulated by the balance of LPA production by autotaxin (ATX) vs. LPA degradation by lipid phosphate phosphatases (LPPs). LPA promotes an inflammatory cycle by increasing the synthesis of cyclooxygenase-2 and multiple inflammatory cytokines that stimulate further ATX production. We aimed to determine whether the anti-inflammatory glucocorticoid (GC) dexamethasone (Dex) functions partly by decreasing the ATX-LPA inflammatory cycle in adipose tissue, a major site of ATX secretion. Treatment of human adipose tissue with 10-1000 nM Dex decreased ATX secretion, increased LPP1 expression, and decreased mRNA expressions of IL-6, TNF-α, peroxisome proliferator-activated receptor (PPAR)-γ, and adiponectin. Cotreatment with rosiglitazone (an insulin sensitizer), insulin, or both abolished Dex-induced decreases in ATX and adiponectin secretion, but did not reverse Dex-induced decreases in secretions of 20 inflammatory cytokines and chemokines. Dex-treated mice exhibited lower ATX activity in plasma, brain, and adipose tissue; decreased mRNA levels for LPA and sphingosine 1-phosphate (S1P) receptors in brain; and decreased plasma concentrations of LPA and S1P. Our results establish a novel mechanism for the anti-inflammatory effects of Dex through decreased signaling by the ATX-LPA-inflammatory axis. The GC action in adipose tissue has implications for the pathogenesis of insulin resistance and obesity in metabolic syndrome and breast cancer treatment.-Meng, G., Tang, X., Yang, Z., Zhao, Y., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Dexamethasone decreases the autotaxin-lysophosphatidate-inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer.

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“…They also found that the average relative protein abundance over all dexamethasone-treated TM cell samples (glaucomatous and nonglaucomatous together) did not show a significant change in fibronectin protein expression. In contrast, Honjo et al, 46 Peng et al, 47 Filla et al, 48 Downloaded from iovs.arvojournals.org on 09/06/2020 and Zhou et al 49 reported that the protein expression of fibronectin was significantly increased after exposing human TM cells to dexamethasone. Additionally, Li et al 50 reported the fibronectin protein secretion to be significantly increased in four human TM cell strains but to be decreased in one human TM cell strain after exposure to dexamethasone (both after 1 and 4 weeks of exposure).…”

Section: Figurementioning

confidence: 95%

The Molecular Processes in the Trabecular Meshwork After Exposure to Corticosteroids and in Corticosteroid-Induced Ocular Hypertension

Liesenborghs

Eijssen

Kutmon

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To identify processes that contribute to corticosteroid-induced ocular hypertension and candidate target genes for treatment. METHODS. A systematic search identified five human microarray datasets investigating the effect of dexamethasone versus a control medium on trabecular meshwork (TM) tissue. After thorough quality control, samples of low quality were removed, and the datasets were integrated. Additionally, a bovine RNA-sequencing dataset allowed to investigate differences in gene expression profiling between cows with and without corticosteroidinduced ocular hypertension (responders vs. nonresponders). The obtained datasets were used as input for parallel pathway analyses. Significantly changed pathways were clustered into functional categories and the results were further investigated. A network visualizing the differences between the responders and nonresponders was created. RESULTS. Seven functional pathway clusters were found to be significantly changed in TM cells exposed to dexamethasone versus a control medium and in TM cells of responders versus nonresponders: collagen, extracellular matrix, adhesion, WNT-signaling, inflammation, adipogenesis, and glucose metabolism. In addition, cell cycle and senescence were only significantly changed in responders versus nonresponders. The network of the differential gene expression between responders and nonresponders shows many connections between the identified processes via shared genes. CONCLUSIONS. Nine functional pathway clusters synthesize the molecular response to dexamethasone exposure in TM cells and are likely to be involved in the pathogenesis of corticosteroid-induced ocular hypertension.

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Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells

Abstract: The results of this study, including the robust induction of ATX by Dex treatment, in association with fibrotic changes and ECM production in HTM cells, collectively suggest a potential role for ATX-LPA pathway in the regulation of aqueous humor outflow and IOP in glaucomatous eyes.

Cited by 40 publications

References 63 publications

Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

Involvement of autotaxin in the pathophysiology of elevated intraocular pressure in Posner-Schlossman syndrome

Dexamethasone decreases the autotaxin‐lysophosphatidate‐inflammatory axis in adipose tissue: implications for the metabolic syndrome and breast cancer

The Molecular Processes in the Trabecular Meshwork After Exposure to Corticosteroids and in Corticosteroid-Induced Ocular Hypertension

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