title: Differential expression and localization of human tissue inhibitors of metalloproteinases in proliferative diabetic retinopathy.
abstract: OBJECTIVE
  Tissue inhibitors of metalloproteinases (TIMPs) block the catalysis by matrix metalloproteinases (MMPs) and have additional biologic activities, including regulation of cell growth and differentiation, apoptosis, angiogenesis and oncogenesis. We investigated the expression levels of all the four human TIMPs and correlated these levels with those of MMP-9 and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR).
  
  
  METHODS
  Vitreous samples from 38 PDR and 21 nondiabetic control patients and epiretinal membranes from 14 patients with PDR and 10 patients with proliferative vitreoretinopathy (PVR) were studied by enzyme-linked immunosorbent assay, Western blot analysis and immunohistochemistry.
  
  
  RESULTS
  Tissue inhibitor of metalloproteinases-1, TIMP-4, MMP-9 and VEGF levels were significantly higher in vitreous samples from PDR patients than in nondiabetic controls (p < 0.0001 for all comparisons), whereas TIMP-2 and TIMP-3 levels did not differ significantly. TIMP-1, TIMP-4, MMP-9 and VEGF levels in PDR with active neovascularization were significantly higher than those in inactive PDR (p < 0.0001, 0.001, 0.013, 0.004, respectively). Significant positive correlations existed between levels of TIMP-1 and levels of TIMP-4 (r = 0.37; p = 0.004), MMP-9 (r = 0.65; p < 0.0001) and VEGF (r = 0.59; p < 0.0001), between levels of TIMP-4 and levels of MMP-9 (r = 0.61; p < 0.0001) and VEGF (r = 0.62; p < 0.0001) and between levels of MMP-9 and VEGF (r = 0.62; p < 0.0001). TIMP-1 and TIMP-3 were expressed in vascular endothelial cells in PDR epiretinal membranes and in myofibroblasts and leucocytes in PDR and PVR epiretinal membranes.
  
  
  CONCLUSIONS
  The differential expression of TIMPs in PDR suggests that among the 4 TIMPs, TIMP-1 and TIMP-4 may be possible biomarkers of disease activity.
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.|Dr. Nasser Al-Rashid Research Chair in Ophthalmology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed M
authors.identifier: http://orcid.org/0000-0003-2226-8617
authors.initials: AM
authors.lastname: Abu El-Asrar
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ajmal
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bittoun
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohammad Mairaj
authors.initials: MM
authors.lastname: Siddiquei
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Mohammad
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mousa
authors.affiliation: Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D003930:Diabetic Retinopathy / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis*; D018630:Vitreoretinopathy, Proliferative / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D014822:Vitreous Body / Q000378:metabolism* / Q000601:surgery; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D015415:Biomarkers; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4
keywords: angiogenesis; matrix metalloproteinases; proliferative diabetic retinopathy; tissue inhibitors of metalloproteinases; vascular endothelial growth factor