Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy

Kousuke Noda, Susumu Ishida, Makoto Inoue, Ken Icbi Obata, Yoshihisa Oguchi, Yasunori Okada, Eiji Ikeda

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Abstract

PURPOSE. To investigate the matrix metalloproteinase (MMP) species and their activation associated with the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS. Sandwich enzyme immunoassays were used to measure concentrations of MMP-1, -2, -3, -7, -8, -9, and -13 in vitreous samples from patients with PDR and nondiabetic vitreoretinal diseases. To evaluate activation ratios of the zymogen of MMP-2 (proMMP-2) and -9 (proMMP-9) in the vitreous samples and fibrovascular tissues, gelatin zymography was performed. Production and tissue localization of MMP-2, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP)-2, and MMP-9 in the fibrovascular tissues were examined by immunohistochemistry. mRNA expression of MT1-MMP in the tissues was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS. Among the seven different MMPs examined in the vitreous samples, only the levels of MMP-2 and -9 were significantly higher in the PDR samples than in the control. However, activation ratios of proMMP-2 (10.6% ± 11.8%) and proMMP-9 (2.5% ± 5.1%) in PDR vitreous samples were low and not significantly different from those of the control. In contrast, high activation ratios of proMMP-2 (54.3% ± 13.6%) and notable activation of proMMP-9 (19.5% ± 7.8%) were observed in the fibrovascular tissues. Immunohistochemical study demonstrated the localization of MMP-2 and -9 in the endothelial cells and glial cells of the fibrovascular tissues. MMP-2 was colocalized with MT1-MMP and TIMP-2, which are an activator and an activation-enhancing factor, respectively, for proMMP-2. RT-PCR analysis indicated the gene expression of MT1-MMP in the tissues. CONCLUSIONS. These data demonstrate that proMMP-2 is efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP and TIMP-2, and suggest the possibility that the activity of MMP-2 and MT1-MMP is involved in the formation of the fibrovascular tissues.

Original languageEnglish
Pages (from-to)2163-2170
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume44
Issue number5
DOIs
Publication statusPublished - 2003 May 1

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Matrix Metalloproteinase 2
Diabetic Retinopathy
Matrix Metalloproteinases
Tissue Inhibitor of Metalloproteinase-2
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 9
Matrix Metalloproteinase 14
Membranes
Reverse Transcription
Polymerase Chain Reaction
Matrix Metalloproteinase 1
Enzyme Precursors
Gelatin
Immunoenzyme Techniques
Neuroglia
Endothelial Cells
Immunohistochemistry
progelatinase
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. / Noda, Kousuke; Ishida, Susumu; Inoue, Makoto; Obata, Ken Icbi; Oguchi, Yoshihisa; Okada, Yasunori; Ikeda, Eiji.

In: Investigative Ophthalmology and Visual Science, Vol. 44, No. 5, 01.05.2003, p. 2163-2170.

Research output: Contribution to journalArticle

Noda, Kousuke ; Ishida, Susumu ; Inoue, Makoto ; Obata, Ken Icbi ; Oguchi, Yoshihisa ; Okada, Yasunori ; Ikeda, Eiji. / Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. In: Investigative Ophthalmology and Visual Science. 2003 ; Vol. 44, No. 5. pp. 2163-2170.
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T1 - Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy

AU - Noda, Kousuke

AU - Ishida, Susumu

AU - Inoue, Makoto

AU - Obata, Ken Icbi

AU - Oguchi, Yoshihisa

AU - Okada, Yasunori

AU - Ikeda, Eiji

PY - 2003/5/1

Y1 - 2003/5/1

N2 - PURPOSE. To investigate the matrix metalloproteinase (MMP) species and their activation associated with the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS. Sandwich enzyme immunoassays were used to measure concentrations of MMP-1, -2, -3, -7, -8, -9, and -13 in vitreous samples from patients with PDR and nondiabetic vitreoretinal diseases. To evaluate activation ratios of the zymogen of MMP-2 (proMMP-2) and -9 (proMMP-9) in the vitreous samples and fibrovascular tissues, gelatin zymography was performed. Production and tissue localization of MMP-2, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP)-2, and MMP-9 in the fibrovascular tissues were examined by immunohistochemistry. mRNA expression of MT1-MMP in the tissues was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS. Among the seven different MMPs examined in the vitreous samples, only the levels of MMP-2 and -9 were significantly higher in the PDR samples than in the control. However, activation ratios of proMMP-2 (10.6% ± 11.8%) and proMMP-9 (2.5% ± 5.1%) in PDR vitreous samples were low and not significantly different from those of the control. In contrast, high activation ratios of proMMP-2 (54.3% ± 13.6%) and notable activation of proMMP-9 (19.5% ± 7.8%) were observed in the fibrovascular tissues. Immunohistochemical study demonstrated the localization of MMP-2 and -9 in the endothelial cells and glial cells of the fibrovascular tissues. MMP-2 was colocalized with MT1-MMP and TIMP-2, which are an activator and an activation-enhancing factor, respectively, for proMMP-2. RT-PCR analysis indicated the gene expression of MT1-MMP in the tissues. CONCLUSIONS. These data demonstrate that proMMP-2 is efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP and TIMP-2, and suggest the possibility that the activity of MMP-2 and MT1-MMP is involved in the formation of the fibrovascular tissues.

AB - PURPOSE. To investigate the matrix metalloproteinase (MMP) species and their activation associated with the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS. Sandwich enzyme immunoassays were used to measure concentrations of MMP-1, -2, -3, -7, -8, -9, and -13 in vitreous samples from patients with PDR and nondiabetic vitreoretinal diseases. To evaluate activation ratios of the zymogen of MMP-2 (proMMP-2) and -9 (proMMP-9) in the vitreous samples and fibrovascular tissues, gelatin zymography was performed. Production and tissue localization of MMP-2, membrane type 1-MMP (MT1-MMP), tissue inhibitor of metalloproteinases (TIMP)-2, and MMP-9 in the fibrovascular tissues were examined by immunohistochemistry. mRNA expression of MT1-MMP in the tissues was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS. Among the seven different MMPs examined in the vitreous samples, only the levels of MMP-2 and -9 were significantly higher in the PDR samples than in the control. However, activation ratios of proMMP-2 (10.6% ± 11.8%) and proMMP-9 (2.5% ± 5.1%) in PDR vitreous samples were low and not significantly different from those of the control. In contrast, high activation ratios of proMMP-2 (54.3% ± 13.6%) and notable activation of proMMP-9 (19.5% ± 7.8%) were observed in the fibrovascular tissues. Immunohistochemical study demonstrated the localization of MMP-2 and -9 in the endothelial cells and glial cells of the fibrovascular tissues. MMP-2 was colocalized with MT1-MMP and TIMP-2, which are an activator and an activation-enhancing factor, respectively, for proMMP-2. RT-PCR analysis indicated the gene expression of MT1-MMP in the tissues. CONCLUSIONS. These data demonstrate that proMMP-2 is efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP and TIMP-2, and suggest the possibility that the activity of MMP-2 and MT1-MMP is involved in the formation of the fibrovascular tissues.

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