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Minireview: Fibronectin in retinal disease.

ABSTRACT: Retinal fibrosis, characterized by dysregulation of extracellular matrix (ECM) protein deposition by retinal endothelial cells, pigment epithelial cells, and other resident cell-types, is a unifying feature of several common retinal diseases. Fibronectin is an early constituent of newly deposited ECM and serves as a template for assembly of other ECM proteins, including collagens. Under physiologic conditions, fibronectin is found in all layers of Bruch's membrane. Proliferative vitreoretinopathy (PVR), a complication of retinal surgery, is characterized by ECM accumulation. Among the earliest histologic manifestations of diabetic retinopathy (DR) is capillary basement membrane thickening, which occurs due to perturbations in ECM homeostasis. Neovascularization, the hallmark of late stage DR as well as exudative age-related macular degeneration (AMD), involves ECM assembly as a scaffold for the aberrant new vessel architecture. Rodent models of retinal injury demonstrate a key role for fibronectin in complications characteristic of PVR, including retinal detachment. In mouse models of DR, reducing fibronectin gene expression has been shown to arrest the accumulation of ECM in the capillary basement membrane. Alterations in matrix metalloproteinase activity thought to be important in the pathogenesis of AMD impact the turnover of fibronectin matrix as well as collagens. Growth factors involved in PVR, AMD, and DR, such as PDGF and TGFβ, are known to stimulate fibronectin matrix assembly. A deeper understanding of how pathologic ECM deposition contributes to disease progression may help to identify novel targets for therapeutic intervention.

SUBMITTER: Miller CG

PROVIDER: S-EPMC5206986 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Project description:Background: Canine intervertebral disc disease (IVDD) represents a significant clinical problem in veterinary medicine, with similarities to the human pathology. Host-derived damage-associated molecular patterns like fibronectin fragments (FnF) that develop during tissue dysfunction may be of specific relevance to IVD pathologies by inducing an inflammatory response in resident cells. Aim: This project aimed to determine the presence and pathobiological role of FnF during IVD herniation in dogs, with a focus on inflammation. Methods: Herniated nucleus pulposus (NP) material from five dogs as well as non-herniated adjacent NP material from three dogs was collected during spinal surgery required due to acute IVD herniation. The presence of different types of FnF were determined by Western blot analysis. NP cells isolated from six herniated canine IVDs were then exposed to 30 kDa FnF. NP cell inflammation and catabolism was examined by investigating the expression of IL-1β, IL-6, IL-8, and COX-2, as well as MMP-1 and MMP-3 by qPCR (all targets) and ELISA (IL-6, PGE2). Results: Amongst multiple sized FnF (30, 35, 45, and >170kDa), N-terminal fragments at a size of ~30 kDa were most consistently expressed in all five herniated IVDs. Importantly, these fragments were exclusively present in herniated, but not in non-herniated IVDs. Exposure of canine NP cells to 500 nM 30 kDa FnF caused a significant upregulation of IL-6 (62.5 ± 79.9, p = 0.032) and IL-8 (53.0 ± 75.7, p = 0.031) on the gene level, whereas IL-6 protein analysis was inconclusive. Donor-donor variation was observed in response to FnF treatment, whereby this phenomenon was most evident for COX-2, with three donors demonstrating a significant downregulation (0.67 ± 0.03, p = 0.003) and three donors showing upregulation (6.9 ± 5.5, p = 0.21). Co-treatment with Sparstolonin B, a TRL-2/TRL-4 antagonist, showed no statistical difference to FnF treatment alone in all tested target genes. Conclusion: Given the presence of the 30 kDa FnF in canine herniated IVDs and the proinflammatory effect of 30 kDa FnF on NP cells, we concluded that the accumulation of FnF may be involved in the pathogenesis of canine IVDD. These results correspond to the findings in humans with IVDD.

Project description:Diabetic retinopathy (DR) has been considered a microvascular disease, but it has become evident that neurodegeneration also plays a key role in this complex pathology. Indeed, this complexity is reflected in its progression which occurs at different rates in different type 2 diabetic (T2D) individuals. Based on this concept, our group has identified three DR progression phenotypes that might reflect the interindividual differences: phenotype A, characterized by low microaneurysm turnover (MAT <6), phenotype B, low MAT (<6) and increased central retinal thickness (CRT); and phenotype C, with high MAT (≥6). In this study, we evaluated the progression of DR neurodegeneration, considering ganglion cell+inner plexiform layers (GCL+IPL) thinning, in 170 T2D individuals followed for a period of 5 years, to explore associations with disease progression or risk phenotypes. Ophthalmological examinations were performed at baseline, first 6 months, and annually. GCL+IPL average thickness was evaluated by optical coherence tomography (OCT). Microaneurysm turnover (MAT) was evaluated using the RetMarkerDR. ETDRS level and severity progression were assessed in seven-field color fundus photography. In the overall population there was a significant loss in GCL+IPL (-0.147 μm/year), independently of glycated hemoglobin, age, sex, and duration of diabetes. Interestingly, this progressive thinning in GCL + IPL reached higher values in phenotypes B and C (-0.249 and -0.238 μm/year, respectively), whereas phenotype A remained relatively stable. The presence of neurodegeneration in all phenotypes suggests that it is the retinal vascular response to the early neurodegenerative changes that determines the course of the retinopathy in each individual. Therefore, classification of different DR phenotypes appears to offer relevant clarification of DR disease progression and an opportunity for improved management of each T2D individual with DR, thus playing a valuable role for the implementation of personalized medicine in DR.

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Minireview: Fibronectin in retinal disease.

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