Expression of Tissue Inhibitor of Metalloproteinase-4 in Normal Human Corneal Cells and Experimental Corneal Neovascularization

Abstract

Purpose: To study the expression of TIMP-4 in cultured corneal cells and in corneal neovascularization. Methods: Human limbo-corneal epithelial cells, fibroblasts, and endothelial cells were cultured in serum-free, PMA- or basic fibroblast growth factor (bFGF)-treated condition. Neovascularization in rat cornea was induced by suturing. The expression of TIMP-4 was examined by immunohistochemistry, Western blot and RT-PCR. Results: TIMP-4 was constitutively expressed in cultured human corneal cells. The expression was only mildly enhanced after mitogen treatment. TIMP-4 immunoreactivity was predominantly expressed in normal rat corneal epithelium, and also in ingrowing blood vessels following suturing, which persisted up to day 28. Increased staining in corneal epithelium and blood vessels were also noted in vascularized human corneas. Conclusions: TIMP-4 is expressed in the cornea, which may play a role in modulating extracellular matrix remodeling associated with corneal wound healing and angiogenesis.

Histopathologic Limbus Evolution After Alkaline Burns

“…Activation of metalloproteinases plays an important role in the stromal repairing process. 27 Interaction between collagenolytic enzymes and collagen synthesis is essential for stromal wound healing. Interleukin-4 plays a significant role in the production of collagen.…”

Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model

“…7 Recent studies have shown that angiogenesis inhibitors, such as endostatin, angiostatin, somatostatin, tissue inhibitor of metalloproteinase-3, peptide derived from thrombospondin-1, prolactin and brain-specific angiogenesis inhibitor 1 (BAI1), can inhibit corneal neovascularization and maintain corneal avascularity. [9][10][11][12][13][14][15][16] GA-binding protein (GABP) is a ubiquitously expressed nuclear transcription factor that is involved in a broad range of cellular processes and that regulates target gene expression in the cell cycle and cellular metabolism. 17 GABP is composed of two subunits: GABPa contains the erythroblast transformation-specific DNA-binding domain, whereas the substitutable subunit, GABPb or GABPg, contains ankyrin repeats and the transcriptional activation domain.…”

Inhibition of Fibroblast-Induced Angiogenic Phenotype of Cultured Endothelial Cells by the Overexpression of Tissue Inhibitor of Metalloproteinase (TIMP)-3

“…To date, all 4 isoforms of TIMPs have been identified in the cornea, and are thought to be involved in the maintenance of corneal avascularity [29,33]. Although TIMP-3 has been reported to inhibit chemotaxis, collagen gel invasion and capillary morphogenesis of ECs in vitro, and to inhibit bFGF-induced angiogenesis in vivo [4], little is known about the expression of TIMP-3 in ECs and the antiangiogenic activity produced by TIMP-3 overexpression.…”