TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration

Tosi, Gian Marco; Neri, Giovanni; Caldi, Elena; Fusco, Fiorella; Bacci, Tommaso; Tarantello, Antonio; Nuti, Elisabetta; Marigliani, Davide; Baiocchi, Stefano; Traversi, Claudio; Barbarino, Marcella; Eandi, Chiara M; Parolini, Barbara; Mundo, Lucia; Santucci, Annalisa; Orlandini, Maurizio; Galvagni, Federico

doi:10.1038/s41598-018-26442-0

Cited by 25 publications

(24 citation statements)

References 33 publications

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“…All three TGF-β isoforms were detected in aqueous and vitreous humor of the human eye ( Figure 2 ), and it was determined that approximately 87% of the vitreal TGF-β is in the latent form [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Although different detection methods were used to measure TGF-β concentrations, all studies agree that TGF-β2, both active and latent, is the predominant isoform in normal aqueous and vitreous humor, and that active TGF-β1 is not detectable [ 33 , 37 , 39 , 40 ]. In human aqueous humor, the ratio among the three active isoforms was estimated to be 1:0.4:0 for β2:β3:β1, respectively [ 39 ].…”

Section: Tgf-β Synthesis and Signaling Pathwaymentioning

confidence: 99%

“…Although different detection methods were used to measure TGF-β concentrations, all studies agree that TGF-β2, both active and latent, is the predominant isoform in normal aqueous and vitreous humor, and that active TGF-β1 is not detectable [ 33 , 37 , 39 , 40 ]. In human aqueous humor, the ratio among the three active isoforms was estimated to be 1:0.4:0 for β2:β3:β1, respectively [ 39 ]. Immunolocalization of TGF-β isoforms in the anterior segment of the eye has evidenced that TGF-β1 is found in the superficial limbal epithelium, in the proximal portion of ciliary processes and in the wall of blood vessels within the ciliary body ( Figure 2 a) [ 41 ].…”

Section: Tgf-β Synthesis and Signaling Pathwaymentioning

confidence: 99%

“…In humans, contrary to what is observed for TGF-β1, aqueous levels of active TGF-β2 are lower in nAMD patients as compared to controls, even after anti-VEGF-A treatment, while TGF-β3 expression remains unchanged [ 39 ]. This observation is made more significant by the fact that TGF-β2 is the predominant isoform in the human eye and seems to be more specific for the activation of SMAD2/3 (antiangiogenic) transcriptional response, because of its dependency on betaglycan for receptor binding and its inability to bind endoglin.…”

Section: Evidence For Antiangiogenic Function Of Tgf-β In Namdmentioning

confidence: 99%

See 2 more Smart Citations

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

Tosi

Orlandini

Galvagni

2018

IJMS

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The multifunctional transforming growth factors-beta (TGF-βs) have been extensively studied regarding their role in the pathogenesis of neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Despite this, their effect remains somewhat controversial. Indeed, both pro- and antiangiogenic activities have been suggested for TGF-β signaling in the development and progression of nAMD, and opposite therapies have been proposed targeting the inhibition or activation of the TGF-β pathway. The present article summarizes the current literature linking TGF-β and nAMD, and reviews experimental data supporting both pro- and antiangiogenic hypotheses, taking into account the limitations of the experimental approaches.

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Section: Tgf-β Synthesis and Signaling Pathwaymentioning

confidence: 99%

Section: Tgf-β Synthesis and Signaling Pathwaymentioning

confidence: 99%

Section: Evidence For Antiangiogenic Function Of Tgf-β In Namdmentioning

confidence: 99%

See 1 more Smart Citation

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

Tosi

Orlandini

Galvagni

2018

IJMS

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“… 63 This family of proteins also has been found to be downregulated in the aqueous of patients with neovascular AMD. 64 TGF-β also has a critical role in immune homeostasis, as dysregulation of this signaling pathway is related to inflammatory diseases and the development of tumors. 65 , 66 Another top-ranked but smaller pathway was digestion and absorption, which refers to digestion of fats, carbohydrates, and proteins in the intestine and movement of the products of digestion out of the lumen of the intestine.…”

Section: Discussionmentioning

confidence: 99%

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

Lynch

Wagner

Palestine

et al. 2020

Trans. Vis. Sci. Tech.

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Purpose To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3–48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03–49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-β family members. Conclusions We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational Relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

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“…The only soluble mediators associated with these 8 pathways (and therefore measurable in AH) are VEGFA, TGFβ1 and Gremlin-1, an inhibitor of TGFβ pathway. Since we recently showed that TGFβ1 is poorly expressed in the AH [ 34 , 35 ], we decided to measure VEGFA concentration. Additionally, GO analysis identified a direct validated regulation of miR-199a-3p on F11 receptor, which has been shown to be involved in the maintenance of the retinal pigment epithelium barrier [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema

Grieco

Sebastiani

Eandi

et al. 2020

IJMS

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We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis.

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TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration

Cited by 25 publications

References 33 publications

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

The Controversial Role of TGF-β in Neovascular Age-Related Macular Degeneration Pathogenesis

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema

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