Ocular TGF-β, Matrix Metalloproteinases, and TIMP-1 Increase with the Development and Progression of Diabetic Retinopathy in Type 2 Diabetes Mellitus

Abstract

Diabetic retinopathy (DR) is a sight-threatening late complication of diabetes mellitus (DM). Even though its pathophysiology has not been fully elucidated, several studies suggested a role for transforming growth factor- (TGF-) β, matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinase (TIMP) in the onset and progression of the disease. Consequently, the aim of this study was to analyze the concentrations of TGF-β1, TGF-β2, TGF-β3, MMP-3, MMP-9, and TIMP-1 in patients with different stages of DR in order to identify stage-specific changes in their concentrations during the progression of the disease. Serum and aqueous humor (AH) samples were collected during intraocular surgery, and eyes were classified into the following groups: healthy controls ( n = 17 ), diabetic patients with non-apparent DR ( n = 23 ), mild/moderate nonproliferative DR (NPDR) ( n = 13 ), and advanced NPDR/proliferative DR (PDR) without vitreal hemorrhage ( n = 14 ). None of the patients had been under anti-VEGF or laser treatment within six months prior to surgery. In the AH, TGF-β1 levels increased in advanced NPDR/PDR by a factor of 5.5 compared to the control group. Similarly, an increase in MMP-3 and TIMP-1 levels in the AH was evident in the later stages of DR, corresponding to a 7.7- and 2.4-fold increase compared to the control group, respectively, whereas serum levels of the studied proteins remained similar. In conclusion, increased concentrations of TGF-β1, MMP-3, and TIMP-1 in the AH, but not in the serum, in advanced NPDR/PDR indicate that the intraocular regulation for these cytokines is independent of the systemic one and suggest their involvement in the progression of DR.

Gene Biomarkers Related to Th17 Cells in Macular Edema of Diabetic Retinopathy: Cutting-Edge Comprehensive Bioinformatics Analysis and In Vivo Validation

“…TIMP-1 is a strong inhibitor of most matrix metalloproteinases (MMP), and the balance between them may be critical to tissue homeostasis in DR ( 69 ). Studies have reported elevated levels of TIMP-1 in vitreous fluid in the PDR, and some studies have shown that the balance between TIMP-1 and MMP may be disrupted early in the onset of DR ( 69 – 71 ). In late NPDR/PDR, the concentration of TIMP-1 in aqueous humor increased, but there was no significant change in serum, indicating that its intraocular regulation was independent of systemic regulation, and that TIMP-1 was involved in the progression of DR ( 71 ).…”

“…Studies have reported elevated levels of TIMP-1 in vitreous fluid in the PDR, and some studies have shown that the balance between TIMP-1 and MMP may be disrupted early in the onset of DR ( 69 – 71 ). In late NPDR/PDR, the concentration of TIMP-1 in aqueous humor increased, but there was no significant change in serum, indicating that its intraocular regulation was independent of systemic regulation, and that TIMP-1 was involved in the progression of DR ( 71 ). BMP-7, a member of BMPs, interacts with TGF- β and participates in the process of tissue degeneration and fibrosis.…”

Effects of the Calix[4]arene Derivative Compound OTX008 on High Glucose-Stimulated ARPE-19 Cells: Focus on Galectin-1/TGF-β/EMT Pathway

“…Similarly, there is increasing evidence that transforming growth factor beta (TGF-β) signaling plays a critical role in DR. In fact, TGF-β1 expression in DR patients, DR rats, and high glucose-incubated human retinal endothelial cells (HRECs) and human adult retinal pigment epithelial cells (ARPE-19) is increased [ 4 , 5 , 6 , 7 ], possibly representing a target of anti-fibrotic therapy during DR.…”

Role of Autotaxin in High Glucose-Induced Human ARPE-19 Cells

“…In vitro studies have used the high glucose (HG)-induced human retinal pigment epithelial (RPE) cell line ARPE-19 to investigate the DR pathogenesis [ 10 ]. In HG-induced ARPE-19 cells, several pathological changes are associated with DR, including the upregulation of vascular endothelial growth factor (VEGF) [ 11 ]; transforming growth factor (TGF) [ 12 , 13 ]; matrix metalloproteinases [ 14 , 15 , 16 ]; inflammatory cytokines [ 17 ]; oxidative stress [ 18 , 19 , 20 , 21 ]; and genetic factors [ 22 , 23 , 24 ]. However, few studies have investigated the relationship between autotaxin (ATX) and DR.…”