Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing

Kanako Izumi, Daijiro Kurosaka, Takeshi Iwata, Yoshihisa Oguchi, Yasuhiko Tanaka, Yukihiko Mashima, Kazuo Tsubota

Research output: Contribution to journalArticle

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Abstract

PURPOSE. The involvement of downstream messengers of transforming growth factor (TGF)-β in the differentiation of corneal fibroblasts into myofibroblasts was investigated. The effects of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 upregulated by TGF-β were examined in human corneal fibroblasts, and the possible involvement of IGF axis components in corneal wound healing was assessed in a mouse model. METHODS. Human corneal fibroblasts were incubated with TGF-β2 or IGF-I, to investigate IGF-I, IGF-II, IGFBP-3, type I collagen, and α-smooth muscle actin (α-SMA) mRNA, as well as IGFBP-3 protein expression, during myofibroblast differentiation. DNA synthesis was evaluated with a 5-bromo-2́-deoxyuridine (BrdU) incorporation assay. IGFBP-3 mRNA expression, protein expression, and immunolocalization were investigated in mouse corneas after photorefractive keratectomy (PRK). RESULTS. TGF-β2 treatment induced expression of IGF-I and IGFBP-3 mRNA and of IGFBP-3 protein in human corneal fibroblasts. TGF-β2 and IGF-I both stimulated expression of type I collagen. TGF-β2 but not IGF-I potently stimulated α-SMA mRNA expression. IGF-I potently stimulated basal DNA synthesis, whereas IGFBP-3 inhibited it. IGF-I potently stimulated proliferation of TGF-β2-activated myofibroblasts without reversing the activated fibrogenic phenotype, whereas IGFBP-3 suppressed IGF-I-induced proliferation of corneal fibroblasts. IGFBP-3 mRNA and protein increased in mouse corneas soon after PRK, when in vivo immunostaining of the corneas showed expression of IGFBP-3 in the deep layer of the corneal stroma. CONCLUSIONS. These results suggest that during corneal wound healing, TGF-β stimulates IGF axis components, whereas IGFBP-3 may modulate IGF-I-induced myofibroblast proliferation to suppress corneal mesenchymal overgrowth.

Original languageEnglish
Pages (from-to)591-598
Number of pages8
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number2
DOIs
Publication statusPublished - 2006 Feb

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Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Wound Healing
Transforming Growth Factors
Fibroblasts
Myofibroblasts
Messenger RNA
Cornea
Photorefractive Keratectomy
Somatomedins
Collagen Type I
Proteins
Corneal Stroma
Insulin-Like Growth Factor II
DNA
Bromodeoxyuridine
Smooth Muscle
Actins

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing. / Izumi, Kanako; Kurosaka, Daijiro; Iwata, Takeshi; Oguchi, Yoshihisa; Tanaka, Yasuhiko; Mashima, Yukihiko; Tsubota, Kazuo.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 2, 02.2006, p. 591-598.

Research output: Contribution to journalArticle

Izumi, Kanako ; Kurosaka, Daijiro ; Iwata, Takeshi ; Oguchi, Yoshihisa ; Tanaka, Yasuhiko ; Mashima, Yukihiko ; Tsubota, Kazuo. / Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 2. pp. 591-598.
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T1 - Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing

AU - Izumi, Kanako

AU - Kurosaka, Daijiro

AU - Iwata, Takeshi

AU - Oguchi, Yoshihisa

AU - Tanaka, Yasuhiko

AU - Mashima, Yukihiko

AU - Tsubota, Kazuo

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N2 - PURPOSE. The involvement of downstream messengers of transforming growth factor (TGF)-β in the differentiation of corneal fibroblasts into myofibroblasts was investigated. The effects of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 upregulated by TGF-β were examined in human corneal fibroblasts, and the possible involvement of IGF axis components in corneal wound healing was assessed in a mouse model. METHODS. Human corneal fibroblasts were incubated with TGF-β2 or IGF-I, to investigate IGF-I, IGF-II, IGFBP-3, type I collagen, and α-smooth muscle actin (α-SMA) mRNA, as well as IGFBP-3 protein expression, during myofibroblast differentiation. DNA synthesis was evaluated with a 5-bromo-2́-deoxyuridine (BrdU) incorporation assay. IGFBP-3 mRNA expression, protein expression, and immunolocalization were investigated in mouse corneas after photorefractive keratectomy (PRK). RESULTS. TGF-β2 treatment induced expression of IGF-I and IGFBP-3 mRNA and of IGFBP-3 protein in human corneal fibroblasts. TGF-β2 and IGF-I both stimulated expression of type I collagen. TGF-β2 but not IGF-I potently stimulated α-SMA mRNA expression. IGF-I potently stimulated basal DNA synthesis, whereas IGFBP-3 inhibited it. IGF-I potently stimulated proliferation of TGF-β2-activated myofibroblasts without reversing the activated fibrogenic phenotype, whereas IGFBP-3 suppressed IGF-I-induced proliferation of corneal fibroblasts. IGFBP-3 mRNA and protein increased in mouse corneas soon after PRK, when in vivo immunostaining of the corneas showed expression of IGFBP-3 in the deep layer of the corneal stroma. CONCLUSIONS. These results suggest that during corneal wound healing, TGF-β stimulates IGF axis components, whereas IGFBP-3 may modulate IGF-I-induced myofibroblast proliferation to suppress corneal mesenchymal overgrowth.

AB - PURPOSE. The involvement of downstream messengers of transforming growth factor (TGF)-β in the differentiation of corneal fibroblasts into myofibroblasts was investigated. The effects of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 upregulated by TGF-β were examined in human corneal fibroblasts, and the possible involvement of IGF axis components in corneal wound healing was assessed in a mouse model. METHODS. Human corneal fibroblasts were incubated with TGF-β2 or IGF-I, to investigate IGF-I, IGF-II, IGFBP-3, type I collagen, and α-smooth muscle actin (α-SMA) mRNA, as well as IGFBP-3 protein expression, during myofibroblast differentiation. DNA synthesis was evaluated with a 5-bromo-2́-deoxyuridine (BrdU) incorporation assay. IGFBP-3 mRNA expression, protein expression, and immunolocalization were investigated in mouse corneas after photorefractive keratectomy (PRK). RESULTS. TGF-β2 treatment induced expression of IGF-I and IGFBP-3 mRNA and of IGFBP-3 protein in human corneal fibroblasts. TGF-β2 and IGF-I both stimulated expression of type I collagen. TGF-β2 but not IGF-I potently stimulated α-SMA mRNA expression. IGF-I potently stimulated basal DNA synthesis, whereas IGFBP-3 inhibited it. IGF-I potently stimulated proliferation of TGF-β2-activated myofibroblasts without reversing the activated fibrogenic phenotype, whereas IGFBP-3 suppressed IGF-I-induced proliferation of corneal fibroblasts. IGFBP-3 mRNA and protein increased in mouse corneas soon after PRK, when in vivo immunostaining of the corneas showed expression of IGFBP-3 in the deep layer of the corneal stroma. CONCLUSIONS. These results suggest that during corneal wound healing, TGF-β stimulates IGF axis components, whereas IGFBP-3 may modulate IGF-I-induced myofibroblast proliferation to suppress corneal mesenchymal overgrowth.

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