Journal of Pharmacological Sciences | |
Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin | |
Hiroyuki Ishikawa3  Shozaburo Hata3  Mitsutoki Hatta1  Kazuhiko Okamura2  Jun Yamazaki1  | |
[1] Department of Physiological Science & Molecular Biology, Fukuoka Dental College, Japan;Department of Morphological Biology, Fukuoka Dental College, Japan;Department of Oral Growth & Development, Fukuoka Dental College, Japan | |
关键词: keratinocyte; fibroblast; transforming growth factor-β1; αv-integrin; matrix metalloproteinase; | |
DOI : 10.1254/jphs.13209FP | |
学科分类:药学 | |
来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society | |
【 摘 要 】
References(53)Cited-By(6)Supplementary materials(1)Transforming growth factor-β1 (TGF-β1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGF-β1 released by keratinocytes in efforts to identify promising pharmacological approaches for the prevention of hypertrophic scar formation. A three-dimensional collagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor–dependent increase in α-smooth muscle actin (α-SMA) immunostaining and mRNA levels in fibroblasts. Latent TGF-β1 was found to be localized suprabasally and secreted. α-SMA expression was inhibited by an anti-αv-integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a two-dimensional fibroblast culture, α-SMA expression depended on the production of endogenous TGF-β1 and required αv-integrin or MMP for the response to recombinant latent TGF-β1. In keratinocyte-conditioned medium, MMP-dependent latent TGF-β1 secretion was detected. Applying this medium to the fibroblast culture enhanced α-SMA production. This effect was decreased by GM6001, the anti-αv-integrin antibody, or the preabsorption of latent TGF-β1. These results indicate that keratinocytes secrete latent TGF-β1, which is liberated to fibroblasts over distance and is activated to produce α-SMA with the aid of a positive-feedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model.
【 授权许可】
Unknown
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
RO201911300026344ZK.pdf | 2199KB | download |