Wnt Modulators in the Aqueous Humor Are Associated With Outer Retinal Damage Severity in Patients With Neovascular Age-Related Macular Degeneration

Park, Kyu Hyung; Choi, Ae Jin; Yoon, Jang Ho; Lim, Daehan; Woo, Se Joon; Park, Sang Jun; Kim, Hyung Chan; Chung, Hyewon

doi:10.1167/iovs.14-14566

Cited by 16 publications

(16 citation statements)

References 35 publications

(43 reference statements)

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“…A longitudinal prospective study of kallistatin levels in different stages of AMD will clarify whether kallistatin could be used as a biomarker of AMD. Recently, aqueous Wnt signaling modulators, Wnt inhibitory factor 1 (WIF-1) and Dickkopf 3 (DKK-3) are reported significantly higher in neovascular AMD patients, the high WIF-1 levels are also associated with disrupted length of photoreceptor inner and outer segments [ 56 ]. This finding supports the implication of Wnt signaling in photoreceptor integrity and AMD.…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

et al. 2015

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BackgroundThe wingless-type MMTV integration site (Wnt) signaling is a group of signal transduction pathways. In canonical Wnt pathway, Wnt ligands bind to low-density lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6), resulting in phosphorylation and activation of the receptor. We hypothesize that canonical Wnt pathway plays a role in the retinal lesion of age-related macular degeneration (AMD), a leading cause of irreversible central visual loss in elderly.MethodsWe examined LRP6 phosphorylation and Wnt signaling cascade in human retinal sections and plasma kallistatin, an endogenous inhibitor of the Wnt pathway in AMD patients and non-AMD subjects. We also used the Ccl2−/−/Cx3cr1−/−/rd8 and Ccl2−/−/Cx3cr1gfp/gfp mouse models with AMD-like retinal degeneration to further explore the involvement of Wnt signaling activation in the retinal lesions in those models and to preclinically evaluate the role of Wnt signaling suppression as a potential therapeutic option for AMD.ResultsWe found higher levels of LRP6 (a key Wnt signaling receptor) protein phosphorylation and transcripts of the Wnt pathway-targeted genes, as well as higher beta-catenin protein in AMD macula compared to controls. Kallistatin was decreased in the plasma of AMD patients. Retinal non-phosphorylated-β-catenin and phosphorylated-LRP6 were higher in Ccl2−/−/Cx3cr1−/−/rd8 mice than that in wild type. Intravitreal administration of an anti-LRP6 antibody slowed the progression of retinal lesions in Ccl2−/−/Cx3cr1−/−/rd8 and Ccl2−/−/Cx3cr1gfp/gfp mice. Electroretinography of treated eyes exhibited larger amplitudes compared to controls in both mouse models. A2E, a retinoid byproduct associated with AMD was lower in the treated eyes of Ccl2−/−/Cx3cr1−/−/rd8 mice. Anti-LRP6 also suppressed the expression of Tnf-α and Icam-1 in Ccl2−/−/Cx3cr1−/−/rd8 retinas.ConclusionsWnt signaling may be disturbed in AMD patients, which could contribute to the retinal inflammation and increased A2E levels found in AMD. Aberrant activation of canonical Wnt signaling might also contribute to the focal retinal degenerative lesions of mouse models with Ccl2 and Cx3cr1 deficiency, and intravitreal administration of anti-LRP6 antibody could be beneficial by deactivating the canonical Wnt pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0683-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

et al. 2015

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“…Some of the most prevalent eye diseases such as glaucoma (Agnifili et al, 2015; Goyal et al, 2014), neovascular AMD (Kang et al, 2014; Liu et al, 2016; Park et al, 2014), diabetes-induced eye diseases (Hillier et al, 2016; Vujosevic et al, 2015, 2016), and uveitis (Haasnoot et al, 2016; Kalinina Ayuso et al, 2013), to name a few, have been investigated for biomarker content in the AH. Although the vast majority of nucleic acid and lipid biomarkers, and some of the protein biomarkers identified in AH were most likely exosome-associated, very little attention has been directed to the exosome-specific biomarkers.…”

Section: Exosome Biomarkers For Eye Diseasesmentioning

confidence: 99%

Roles of exosomes in the normal and diseased eye

Klingeborn

Dismuke

Rickman

et al. 2017

Progress in Retinal and Eye Research

137

127

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Exosomes are nanometer-sized vesicles that are released by cells in a controlled fashion and mediate a plethora of extra- and intercellular activities. Some key functions of exosomes include cell-cell communication, immune modulation, extracellular matrix turnover, stem cell division/differentiation, neovascularization and cellular waste removal. While much is known about their role in cancer, exosome function in the many specialized tissues of the eye is just beginning to undergo rigorous study. Here we review current knowledge of exosome function in the visual system in the context of larger bodies of data from other fields, in both health and disease. Additionally, we discuss recent advances in the exosome field including use of exosomes as a therapeutic vehicle, exosomes as a source of biomarkers for disease, plus current standards for isolation and validation of exosome populations. Finally, we use this foundational information about exosomes in the eye as a platform to identify areas of opportunity for future research studies.

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“…Among these, Wif1 has perhaps received the least recognition. Its function is, however, implicated in various crucial processes during eye development and homeostasis (Hunter et al, 2004; Park et al, 2014), neurogenesis and axon extension (Hunter et al, 2004; Nakaya et al, 2008), lung and anorectal development (Xu et al, 2011; Ng et al, 2014), tooth morphogenesis (Lee et al, 2015), chondrogenesis (Surmann-Schmitt et al, 2009), stem cell maintenance (Ding et al, 2008; Nakatsu et al, 2011), regeneration and cancer (Wissmann et al, 2003; Lim et al, 2017; Figure 1). The Wif1 protein structure exhibits intriguing features suggesting that its full spectrum of action and importance has yet to be uncovered.…”

Section: Introductionmentioning

confidence: 99%

An Eye on the Wnt Inhibitory Factor Wif1

Poggi

Casarosa

Carl

2018

Front. Cell Dev. Biol.

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The coordinated interplay between extrinsic activating and repressing cell signaling molecules is pivotal for embryonic development and subsequent tissue homeostasis. This is well exemplified by studies on the evolutionarily conserved Wnt signaling pathways. Tight temporal and spatial regulation of Wnt signaling activity is required throughout lifetime, from maternal stages before gastrulation until and throughout adulthood. Outside cells, the action of numerous Wnt ligands is counteracted and fine-tuned by only a handful of well characterized secreted inhibitors, such as for instance Dickkopf, secreted Frizzled Related Proteins and Cerberus. Here, we give an overview of our current understanding of another secreted Wnt signaling antagonist, the Wnt inhibitory factor Wif1. Wif1 can directly interact with various Wnt ligands and inhibits their binding to membrane bound receptors. Epigenetic promoter methylation of Wif1, leading to silencing of its transcription and concomitant up-regulation of Wnt signaling, is a common feature during cancer progression. Furthermore, an increasing number of reports describe Wif1 involvement in regulating processes during embryonic development, which so far has not received as much attention. We will summarize our knowledge on Wif1 function and its mode of action with a particular focus on the zebrafish (Danio rerio). In addition, we highlight the potential of Wif1 research to understand and possibly influence mechanisms underlying eye diseases and regeneration.

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Wnt Modulators in the Aqueous Humor Are Associated With Outer Retinal Damage Severity in Patients With Neovascular Age-Related Macular Degeneration

Cited by 16 publications

References 35 publications

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

Roles of exosomes in the normal and diseased eye

An Eye on the Wnt Inhibitory Factor Wif1

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